Method of using triaryl-ethylene derivatives in the treatment and prevention of osteoporosis

ABSTRACT

The present invention relates to a method of using triaryl-ethylene derivatives in the treatment or prevention bone tissue loss or osteoporosis.

This application is a division of application Ser. No. 08/531,885, filedOct. 11, 1995, which is a continuation-in-part of application Ser. No.08/346,111, filed Nov. 29, 1994, now abandoned, which are hereinincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a method of using triaryl-ethylenederivatives in the treatment or prevention osteoporosis or bone tissueloss. Osteoporosis is a significant problem for the developed nations.The term osteoporosis is often used to describe different clinicalsituations. Osteoporosis was first used to describe the syndrome inwhich post-menopausal women tended to suffer vertebral fractures. F.Albright et al., J. Am. Med. Assoc. 116, 2465-2474 (1941). To avoidambiguity, the terms bone tissue loss or osteopenia are used to describethe clinical situation in which loss of bone mass or density hasoccurred in the absence of a fracture.

Osteoporosis is most commonly associated with post-menoapuse and agerelated bone tissue loss. Osteoporosis or bone tissue loss can alsooccur secondarily to various drugs and diseases, including:corticosteroids, anticonvulsants, alcohol, malabsorption syndromes,primary biliary cirrhosis, myeloma, thalassemia, thyrotoxicosis,Cushing's syndrome, Turner's syndrome, and primary hyperparathyroidism.

SUMMARY OF THE INVENTION

The present invention relates to a method of using triaryl-ethylenederivatives in the treatment or prevention bone tissue loss orosteoporosis.

The present invention provides a method of treating or preventing bonetissue loss or osteoporosis in a patient, comprising administering aneffective antiosteoporosis amount of a compound of Formula I: ##STR1##wherein A is a radical of the formula ##STR2## wherein R and R₁ are eachindependently hydrogen or C₁ -C₄ alkyl; and

G is HN, H₃ CN, CH₂, or O;

m is an integer from 4 to 12;

R₂ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, or hydroxy;

R₃ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, hydroxy, or--Y(CH₂)_(p) A₁ in which A₁ is a radical of the formula ##STR3## whereinR₄ and R₅ are each independently hydrogen or C₁ -C₄ alkyl;

G₁ is HN, H₃ CN, CH₂, or O; and p is an integer from 4 to 12;

X is chloro or bromo;

Y is O or NH;

or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method of treating orpreventing bone tissue loss or osteoporosis in a patient, comprisingadministering an effective antiosteoporosis amount of a compound ofFormula II: ##STR4## wherein A is a radical of the formula ##STR5##wherein R and R₁ are each independently hydrogen or C₁ -C₄ alkyl; and

G is HN, H₃ CN, CH₂, or O;

m is an integer from 4 to 12;

R₂ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, or hydroxy;

R₃ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, hydroxy, or--Y(CH₂)_(p) A₁ in which A₁ is a radical of the formula ##STR6## whereinR₄ and R₅ are each independently hydrogen or C₁ -C₄ alkyl;

G₁ is HN, H₃ CN, CH₂, or O; and p is an integer from 4 to 12;

X is chloro or bromo;

Y is O or NH;

or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method of treating orpreventing bone tissue loss or osteoporosis in a patient, comprisingadministering an effective antiosteoporosis amount of a compound of theFormula III: ##STR7## wherein A is a radical of the formula ##STR8##wherein R and R₁ are each independently hydrogen or C₁ -C₄ alkyl; and

G is HN, H₃ CN, CH₂, or O;

w is an integer from 2 to 3;

R₂ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, or hydroxy;

R₃ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, hydroxy, or--Y(CH₂)_(z) A₁ in which A₁ is a radical of the formula ##STR9## whereinY is --NH--

R₄ and R₅ are each independently hydrogen or C₁ -C₄ alkyl;

G₁ is HN, H₃ CN, CH₂, or O; and

z is an integer from 2 to 3;

X is chloro or bromo;

or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method of treating orpreventing bone tissue loss or osteoporosis in a patient, comprisingadministering an effective antiosteoporosis amount of a compound of theFormula IV: ##STR10## wherein A is a radical of the formula ##STR11##wherein R and R₁ are each independently hydrogen or C₁ -C₄ alkyl; and

G is HN, H₃ CN, CH₂, or O;

w is an integer from 2 to 3;

R₂ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, or hydroxy;

R₃ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, hydroxy, or--Y(CH₂)_(z) A₁ in which A₁ is a radical of the formula ##STR12##wherein Y is --NH--

R₄ and R₅ are each independently hydrogen or C₁ -C₄ alkyl;

G₁ is HN, H₃ CN, CH₂, or O; and

z is an integer from 2 to 3;

X is chloro or bromo;

or a pharmaceutically acceptable salt thereof.

In addition the present invention provides a pharmaceutical compositionfor oral administration comprising an effective antiosteoporosis amountof a compound of Formula III or Formula IV in admixture or otherwise inassociation with one or more pharmaceutically acceptable carriers orexcipients.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "C₁ -C₄ alkyl" refers to a saturated, straightor branched chain, hydrocarbon radical of one to four carbon atoms andincludes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl,and the like.

As used herein, the designation "halogen" refers to a bond for which thestereochemistry is not designated.

As used herein, the term "halogen" refers to a fluorine, chlorine,bromine, or iodine atom.

As used herein, the term "C₁ -C₄ alkoxy" refers to a C₁ -C₄ alkylbearing an oxy group and includes methoxy, ethoxy, n-propoxy, n-butoxy,iso-propoxy, iso-butoxy, t-butoxy, and the like.

As used herein, the term "hydroxy" or "hydroxy group" refers to a --OHradical.

As used herein, the term "(CH₂)_(n) " refers to a straight chainalkylene radical of from 2 carbon atoms to 12 carbon atoms for example;ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, and dodecyl.

As used herein, the term "(CH₂)_(m) " refers to a straight chainalkylene radical of from 4 carbon atoms to 12 carbon atoms for example;butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

As used herein, the term "(CH₂)_(p) " refers to a straight chainalkylene radical of from 4 carbon atoms to 12 carbon atoms for example;butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

As used herein, the term "(CH₂)_(w) " refers to a straight chainalkylene radical of from 2 carbon atoms to 3 carbon atoms for example;ethyl and propyl.

As used herein, the term "(CH₂)_(z) " refers to a straight chainalkylene radical of from 2 carbon atoms to 3 carbon atoms for example;ethyl and propyl.

As used herein, the term "pharmaceutically acceptable addition saltrefers to either an acid addition salt or a basic addition salt.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by Formula I or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulfuric and phosphoric acid and acidmetal salts such as sodium monohydrogen orthophosphate and potassiumhydrogen sulfate. Illustrative organic acids which form suitable saltsinclude the mono-, di- and tri-carboxylic acids. Illustrative of suchacids are, for example, acetic, glycolic, lactic, pyruvic, malonic,succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, 2-phenoxybenzoic, and sulfonic acids such asp-toluenesulfonic acid, methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts may be formed, and suchsalts may exist in either a hydrated or substantially anhydrous form.

Compounds of Formula I, Formula II, Formula III, and Formula IV exist asgeometric isomers. Any reference in this application to one of thecompounds represented by Formula I, Formula II, Formula III, and FormulaIV is meant to encompass each of the specific geometric isomers. Thespecific geometric isomers can be separated and recovered by techniquesknown in the art such as chromatography on silica gel, chromatography ona reverse-phase adsorbent, or fractional recrystallization. As is wellknown by one of ordinary skill in the art the Cahn-Ingold-Prelogdesignation of (E)- and (Z)- for isomers of compounds of Formula I,Formula II, Formula III, and Formula IV depends on the nature of Y, X,m, w, p, z, A, A₁, R₂, and R₃. As is apparent to one of ordinary skillin the art compounds of Formula I or II in which the substituent R₃ is--Y(CH₂)_(p) A₁ and p=n and A=A₁ do not exist as geometrical isomers.Similarly, for compounds of Formula III or IV in which the substituentR₃ is --NH(CH₂)_(z) A₁ and w=z and A=A₁ do not exist as geometricalisomers.

As is apparent to one of ordinary skill in the art, the compounds ofFormula I and Formula II include compounds wherein m is an integer from4 to 12. The compounds of Formula III and Formula IV include compoundswherein w is an integer from 2 to 3. Therefore, it is understood that adescription of the preparation of compounds that differ from thecompounds of Formula I and II in that (CH₂)_(m) is instead (CH₂)_(n)wherein n is defined as an integer from 2 to 12 comprehends and providesa description of the preparation of the compounds of Formula I, FormulaII, Formula III, and Formula IV.

Illustrative Examples of compounds encompassed by the present inventioninclude:

(E)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(5-Diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(5-Diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(6-Diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(6-Diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(7-Diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(7-Diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(8-Diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(8-Diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(9-Diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(9-Diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(10-Diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(10-Diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(11-Diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(11-Diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(12-Diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(12-Diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(3-Diethylaminopropylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(3-Diethylaminopropylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(4-Diethylaminobutylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(4-Diethylaminobutylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-bromo-ethylene;

(Z)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-bromo-ethylene;

(E)-1-4-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-bromo-ethylene;

(Z)-1-4-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-bromo-ethylene;

(E)-1-4-(3-Diethylaminopropylamino)phenyl!-1,2-diphenyl-2-bromo-ethylene;

(Z)-1-4-(3-Diethylaminopropylamino)phenyl!-1,2-diphenyl-2-bromo-ethylene;

(E)-1- 4-(4-Diethylaminobutylamino)phenyl!-1,2-diphenyl-2-bromo-ethylene

(Z)-1-4-(4-Diethylaminobutylamino)phenyl!-1,2-diphenyl-2-bromo-ethylene;

1,1-Bis- 4-(4-diethylaminobutoxy)phenyl!-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(3-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(3-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-Diethylaminobutoxy)phenyl!-1-phenyl-2-(4-hydroxy)phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-phenyl-2-(4-hydroxy)phenyl-2-chloro-ethylene;

(E)-1-4-(4-Diethylaminobutoxy)phenyl!-1-phenyl-2-(3-hydroxy)phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-phenyl-2-(3-hydroxy)phenyl-2-chloro-ethylene;

(E)-1- 4-(4-Ethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(4-Ethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(4-Methylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(4-Methylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-(4-Propylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-(4-Propylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(4-Dimethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Dimethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-Dipropylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Dipropylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-Dimethylaminobutoxy)phenyl!-1,2-phenyl-2-phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Dimethylaminobutoxy)phenyl!-1,2-diphenyl-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-Dipropylaminobutoxy)phenyl!-1,2-diphenyl-2-phenyl-2-chloro-ethylene;

(Z)-1-4-(4-Dipropylaminobutoxy)phenyl!-1,2-diphenyl-2-phenyl-2-chloro-ethylene;

(E)-1-4-(4-(Piperidin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(4-(Piperidin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-4-(Piperazin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-4-(Piperazin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1- 4-4-(4-Methylpiperazin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1- 4-4-(4-Methylpiperazin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(4-(Morpholin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(4-(Morpholin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(E)-1-4-(4-(Pyrrolidin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene;

(Z)-1-4-(4-(Pyrrolidin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

The compounds of Formula I and II in which Y is O can be prepared asdescribed in Scheme A. All substituents, unless otherwise indicated, arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. ##STR13##

In Scheme A, step a, an appropriate triaryl-ethylene of structure 1 ischlorinated or brominated to give a halotriaryl-ethylene of structure 2.

An appropriate triaryl-ethylene of the structure 1 is one in which R₈ ishydrogen, an ω-haloalkyl group, Z(CH₂)_(m) -- in which Z may be achlorine atom, a bromine atom, or a iodine atom and m is as desired inthe final product, or a suitable hydroxy protecting group; R₆ is asdefined for R₂, or R₆ is a suitably protected hydroxy which afterdeprotection provide compounds of Formula I and Formula II in which R₂is a hydroxy group; and R₇ is as defined for R₃, or R₇ is a suitablyprotected hydroxy which after deprotection provide compounds of FormulaI and Formula II in which R₃ is a hydroxy group, or provides anintermediate for the preparation of a compound of Formula I and FormulaII in which R₃ is --O(CH₂)_(p) A₁ wherein p=m and A=A₁ ; or R₇ is asuitably protected hydroxy which allows for removal in a sequentialmanner providing an intermediate for the preparation of compounds ofFormula I and Formula II in which R₃ is --O(CH₂)_(p) A₁ wherein p≠m andeither A=A₁ or A≠A₁, or in which R₃ is --O(CH₂)_(p) A₁ wherein p=m andA≠A₁. The selection, use, removal, and sequential removal of suitablehydroxy protecting groups, such as benzyl, p-methoxybenzyl, methyl,t-butyldimethylsilyl, and acetyl, is well known and appreciated in theart and described in Protecting Groups in Organic Synthesis by T.Greene.

For example, an appropriate triaryl-ethylene of structure 1 is contactedwith a molar excess of chlorine, bromine, N-chlorosuccinimide, orN-bromosuccinimide in a suitable solvent, such as chloroform,chlorobenzene, or dichloromethane. The reaction is carried out attemperatures from ambient temperature to the reflux temperature of thesolvent. After stirring for from 1-72 hours the product can be isolatedand purified by techniques well known in the art. For example, thereaction mixture can be concentrated in vacuo and the product purifiedby chromatography on silica gel eluting with a suitable organic solvent.The material obtained can be further purified, if desired, byrecrystallization from a suitable organic solvent to give ahalo-triaryl-ethylene of structure 2.

As is appreciated by one of ordinary skill in the art, when ahalo-triaryl-ethylene of structure 2 is derived from a triaryl-ethyleneof structure 1 in which R₈ is a suitable hydroxy protecting group, theprotecting group is removed before step b can be carried out. When ahalo-triaryl-ethylene of structure 2 is derived from a triaryl-ethyleneof structure 1 in which R₈ is a suitable protecting group and R₇ is asuitably protected hydroxy either the protecting groups are removedbefore step b is carried out or they are removed in a sequential manner.When the protecting groups are removed in a sequential mannerintermediates are provided for the preparation of compounds of Formula Iand Formula II in which R₃ is --O(CH₂)_(p) A₁ wherein p≠m and eitherA=A₁ or A≠A₁ and in which R₃ is --O(CH₂)_(p) A₁ wherein p=m and A≠A₁.

In Scheme A, step b, a halo-triaryl-ethylene of structure 2 is contactedwith an appropriate dihaloalkane to form a ω-haloalkoxy-triaryl-ethyleneof structure 3.

An appropriate dihaloalkane, Z(CH₂)_(m) Z₁, is one in which Z and Z₁each may be independently a chlorine atom, a bromine atom, or a iodineatom and m is as desired in the final product of Formula I and FormulaII.

For example, a halo-triaryl-ethylene of structure 2 is contacted with a1.1 to 10 fold molar excess of an appropriate dihaloalkane. The reactionis carried out in the presence of a suitable base, such as sodiumethoxide, sodium methoxide, potassium hydroxide, sodium hydroxide, andsodium carbonate. The reaction is carried out in a solvent, such asethanol, methanol, tetrahydrofuran, acetonitrile, dimethylformamide, ordimethyl sulfoxide. The reaction is carried out at temperatures of from0° C. to the refluxing temperature of the solvent. For compounds ofstructure 2 in which R₈ is hydrogen and R₇ is a hydroxy group the use1.1 molar equivalents of an appropriate dihaloalkane and a suitable baseallows for the preparation of a compound of Formula I and Formula II inwhich R₇ is a hydroxy group. For compounds of structure 2 in which R₈ ishydrogen and R₇ is a hydroxy group the use of from 2 to 10 molarequivalents of an appropriate dihaloalkane and a suitable base gives anbis-ω-haloalkoxy-triaryl-ethylene which is an intermediate in theproduction of a compound of Formula I and Formula II in which R₃ is--O(CH₂)_(p) A₁ wherein p=m and A=A₁. A ω-haloalkoxy-triaryl-ethylene ofstructure 3 may be isolated from the reaction zone by evaporation andextraction and may be purified by methods well known in the art, such aschromatography and recrystallization.

In Scheme A, step c, ω-haloalkoxy-triaryl-ethylene of structure 3 iscontacted with an appropriate amine, HNRR₁, in which R and R₁ are asdefined above, morpholine, piperidine, piperazine, 4-methylpiperazine,or pyrrolidine to give ω-aminoalkoxy-triaryl-ethylene of structure 4.

For example, ω-haloalkoxy-triaryl-ethylene of structure 2 is contactedwith a large molar excess of an appropriate amine in a solvent, such asethanol, methanol, water, ethanol/water mixtures, or methanol/watermixtures. A large molar excess of amine is used so that the amine canalso acts as a base to take up the acid liberated in the reaction. Thereaction may be carried out in the presence of a suitable catalyst, suchas potassium iodide. The reaction vessel may be sealed to prevent theescape of volatile amines. The reaction mixture is heated totemperatures of from 40° C. to 100° C. For compounds of structure 3 inwhich R₇ is a ω-haloalkoxy group the use of an additional portion of anappropriate amine gives a bis-ω-aminoalkoxy-triaryl-ethylene which is acompound of Formula I and Formula II in which R₃ is --O(CH₂)_(p) A₁wherein p=m and A=A₁. The product can be isolated and purified bytechniques well known in the art. For example, the reaction mixture canbe concentrated in vacuo and the product purified by techniques wellknown in the art, such as salt formation, chromatography eluting with asuitable solvent, or recrystallization from a suitable organic solvent.

In Scheme A, step a, may be carried out before or after steps b and care carried out.

In Scheme A, optional step d, for a ω-aminoalkoxy-triaryl-ethylene ofstructure 4 in which R₆ or R₇ is a protected hydroxy group may bedeprotected to provide ω-aminoalkoxy-triaryl-ethylene of structure 5 inwhich either, R₂ or R₃, or R₂ and R₃, are hydroxy as desired in thefinal product of Formula I and Formula II. As is appreciated by oneskilled in the art the compounds of Formula I and Formula II in which R₃is hydroxy can be, by sequentially performing the steps of Scheme A,used as intermediates for preparing compounds of Formula I and FormulaII in which R₃ is --O(CH₂)_(p) A₁ wherein p≠m and either A=A₁ or A≠A₁ orin which R₃ is --O(CH₂)_(p) A₁ wherein p=m and A≠A₁.

The selection, use, removal, and sequential removal of suitable hydroxyprotecting groups is well known and appreciated in the art and describedin Protecting Groups in Organic Synthesis by T. Greene.

In Scheme A, step e, the isomers of a ω-aminoalkoxy-triaryl-ethylene ofstructure 4 or 5 can be separated to give a(E)-ω-aminoalkoxy-triaryl-ethylene of structure 4 or 5 and the(Z)-ω-aminoalkoxy-triaryl-ethylene of structure 4 or 5.

For example, the isomers of compounds of structure 5 can be separatedand purified by high-performance liquid chromatography orrecrystallization of salt to give a (E)-ω-aminoalkoxy-triaryl-ethyleneand a (Z)-ω-aminoalkoxy-triaryl-ethylene.

Pharmaceutically acceptable salts of a(E)-ω-aminoalkoxy-triaryl-ethylene of or of a(Z)-ω-aminoalkoxy-triaryl-ethylene can be formed in an additional stepas is well known and practiced in the art.

The following examples present typical syntheses as described in SchemeA. These examples are understood to be illustrative only and are notintended to limit the scope of the invention in any way. As used in thefollowing examples, the following terms have the meanings indicated:"kg" refers to kilograms, "g" refers to grams, "mg" refers tomilligrams, "mmol" refers to millimoles, "mol" refers to moles, "mL"refers to milliliters, "L" refers to liters, "°C." refers to degreesCelsius, "R_(f) " refers to retention factor, "mp" refers to meltingpoint, "HPLC" refers to high performance liquid chromatography.

EXAMPLE 1

(E and Z)-1- (4-Hydroxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1- (4-hydroxy)phenyl!-1,2-diphenyl-ethylene Cacchi etal, Tet. Lets. 25, 3137-3140 (1984)! (0.90 g, 3.31 mmol) andN-chlorosuccinimide (0.486 g, 3.64 mmol) in chloroform (20 mL). Heat toreflux and allow to stir at reflux for 48 hours. Evaporate in vacuo.Chromatograph on silica gel eluting with 20% ethyl acetate/hexane togive the title compound as a solid: mp; 127°-129° C.

EXAMPLE 2

(E and Z)-1- 4-(4-Chlorobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1- (4-hydroxy)phenyl!-1,2-diphenyl-2-chloro-ethylene(15.0 g, 49.0 mmol) and 4-bromo-1-chlorobutane (35 g, 200 mmol) inethanol (250 mL). Add sodium methoxide (2.75 g, 50.0 mmol). Heat toreflux under an inert atmosphere. After 5 hours concentrate on a steambath to obtain a residue. Partition the residue between diethyl etherand 10% sodium hydroxide. Separate the layers and dry the organic layerover MgSO₄, filter, and evaporate in vacuo to give the title compoundwhich is taken on to the next step without further purification.

EXAMPLE 3

(E and Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (19.0 g, 47.8mmol), diethylamine (20 mL, 193 mmol), and ethanol (100 mL). Seal in areaction vessel and heat to 80° C. for 48 hours. Cool to ambienttemperature and carefully open the pressure vessel. Concentrate in vacuoto obtain a residue. Dissolve the residue in butanone and add citricacid (9.0 g, 47 mmol). Filter to give a mixture of the isomers as theircitric acid salts. Dissolve (E and Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene citricacid salts (1.5 g) in 1/1 acetonitrile/water and adjust the pH to 9 with2M aqueous sodium hydroxide. Extract with chloroform and evaporate togive a mixture of the isomers as a residue. Separate the isomers byHPLC, 90 mg per injection, using a Waters and Associates μPorasil column(19 mm by 300 mm), eluting with 80/20/0.2chloroform/hexane/triethylamine at 15 mL/minute to give (Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(E)-1- 4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 3.1

(E and Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt

Combine 4-hydroxybenzophenone (347 g, 1.75 mol) and methanol (3.5 L).Heat to 50° C. and add a solution of sodium ethanolate in ethanol (718mL, 21% by weight, 1.92 mol) over 20 minutes. Heat to reflux and add1-bromo-4-chlorobutane (600 g, 3.5 mol) over 30 minutes. After 18 hours,cool the reaction mixture and evaporate in vacuo to obtain a residue.

Add ethyl acetate (5 L) to give a solid. Filter and extract the filtratewith aqueous 10% sodium hydroxide solution and aqueous saturated sodiumchloride solution. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give 4-(4-chlorobutoxy)benzophenone.

Combine 4-(4-chlorobutoxy)benzophenone (740 g, 1.59 mol), diethylamine(3.7 L), and potassium iodide (50 g) in water (3.7 L). Heat to reflux.After 19 hours, evaporate the reaction mixture in vacuo to give anaqueous residue. Extract two times with ethyl acetate. Extract thecombined organic layers with aqueous 10% hydrochloric acid solution andseparate the acidic aqueous layer. Combine the acidic aqueous layer andethyl acetate. Slowly add aqueous 10% sodium hydroxide solution untilthe pH of the aqueous layer is about 9. Separate the organic layer,extract twice with water and then aqueous saturated sodium chloridesolution. Dry the organic layer over MgSO₄, filter, and evaporate invacuo to give 4-(4-diethylaminobutoxy)benzophenone.

Combine 4-(4-diethylaminobutoxy)benzophenone (400 g, 1.13 mol) andtetrahydrofuran (4 L). Add a solution of benzylmagnesium chloride (1.1L, 2.0M in tetrahydrofuran, 2.2 mol) over about 30 minutes. After 1hour, heat to reflux. After 2 hours, cool to ambient temperature.Cautiously add aqueous saturated ammonium chloride solution (4 L) and aprecipitate forms. Filter the reaction mixture, rinse withtetrahydrofuran, and extract the filtrate with aqueous saturated sodiumchloride solution. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Combine the residue and butanone.Add citric acid (250 g, 1.3 mol) and cool to give a solid. Collect thesolid by filtration rinse with diethyl ether and dry to give1-(4-diethylaminobutoxy)phenyl-1,2-diphenyl ethanol citrate salt.

Combine 1-(4-diethylaminobutoxy)phenyl-1,2-diphenyl ethanol citrate salt(550 g, 0.90 mol)and water (2.2 L). Heat to 75° C. After a solution isobtained, cool to 10° C. Adjust the pH to about 10.0 using aqueous 25%sodium hydroxide. Extract three times with diethyl ether. Combine theorganic layers and extract with water and aqueous saturated sodiumchloride solution. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Combine the residue and methanol(1 L) and aqueous 3M hydrochloric acid solution (2.2 L). Heat to reflux.After 2 hours, distill to remove most of the methanol and cool theresulting reaction mixture to ambient temperature. After 18 hours,adjusting the pH to about 10 using aqueous 25% sodium hydroxide solutionwhile maintaining the temperature of the reaction mixture at 20° C.Extract the reaction mixture three times with diethyl ether. Combine theorganic layers, extract with water and aqueous saturated sodium chloridesolution. Dry the organic layers over MgSO₄, filter, and evaporate invacuo to give a residue. Combine the residue with methanol (3.2 L) andadd a methanolic hydrochloric acid solution until wet Congo Red papergives a positive test for excess acid. Evaporate in vacuo to give aresidue. Two times, add chloroform and evaporate in vacuo to give (E andZ)-1-(4-diethylaminobutoxy)phenyl-1,2-diphenyl ethylene hydrochloricacid salt.

Combine (E and Z)-1-(4-diethylaminobutoxy)phenyl-1,2-diphenyl ethylenehydrochloric acid salt (449 g, 0.9 mol) and chloroform (1.6 L). Add acold (5° C.) solution of chlorine (68.4 g, 0.96 mol) in carbontetrachloride (3.18 kg) over about 20 minutes while maintaining thetemperature of the reaction mixture below 20° C. After 18 hours, heat toreflux. After 2 hours, cool to ambient temperature and evaporate invacuo to give the title compound.

EXAMPLE 3.2

(E and Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt

Combine 4-hydroxybenzophenone (8 kg, 57.6 mol), potassium carbonate (8kg, 57.6 mol), and 1-bromo-4-chlorobutane (8.384 kg, 48.9 mol) inacetone (40 L). Heat to reflux. After 20 hours, cool the reactionmixture and filter. Rinse the filter cake with acetone and evaporate thefiltrate in vacuo to obtain 4-(4-chlorobutoxy) benzophenone.

Combine 4-(4-chlorobutoxy)benzophenone (8.1 kg, 13.47 mol) andtetrahydrofuran (60 L). Add a solution of benzylmagnesium chloride (21L, 1.67M in tetrahydrofuran, 35 mol) over about 2.5 hours. After 2hours, cautiously add aqueous saturated ammonium chloride solution (9 L)over about 1 hour and a precipitate forms. Filter the reaction mixture,rinse with tetrahydrofuran, and extract the filtrate with aqueoussaturated sodium chloride solution. Evaporate the separated organiclayer in vacuo to give 1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethanol.

Combine 1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethanol (17.0 kg, 20.2mol) and methanol (30 L). Add aqueous 3M hydrochloric acid solution (40L). Heat to reflux. After 2 hours, remove most of the methanol bydistillation and cool the aqueous reaction mixture. Extract withchloroform. Extract the organic layer with aqueous saturated sodiumcarbonate solution. Separate the organic layer and evaporate in vacuo togive (E and Z)-1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethylene.

Combine (E and Z)-1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethylene (20.2mol) and chloroform (60 L). Add N-chlorosuccinimide (7 kg, 52.4 mol).Heat to reflux. After 18 hours, cool to ambient temperature and addwater. Separate the organic layer and extract with aqueous saturatedsodium carbonate solution. Separate the organic layer and evaporate invacuo to give (E and Z)-1-(4-chlorobutoxy)phenyl-2-chloro-1,2-diphenylethylene.

Combine (E and Z)-1-(4-chlorobutoxy)phenyl-2-chloro-1,2-diphenylethylene (20.2 mol), diethylamine (25 L, 241.7 mol), and potassiumiodide (3.5 kg, 21.1 mol) in water (15 L). Heat to reflux. After 18hours, evaporate the reaction mixture in vacuo to give an aqueousresidue. Extract two times with ethyl acetate. Evaporate the organiclayer in vacuo to give a residue. Combine the residue and acetone (50L). Add a solution of citric acid (8 kg) in acetone (40 L). Heat to forma solution and cool to give solid. Collect the solid by filtration,rinse with acetone, and dry to give (E and Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene citratesalt.

Combine (E and Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene citratesalt (15.1 kg, 24.1 mol), sodium hydroxide (3.0 kg, 75 mol), and water(20 L). Extract with ethyl acetate. Separate the organic layer and dryazeotropically at 78° C. Cool the organic layer to 15° C., addhydrochloric acid gas until an acidic solution is obtained. Evaporate invacuo to obtain the title compound.

EXAMPLE 4

(E)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR14##

Combine citric acid (164.7 mg, 0.86 mmol) and ethanol (3 mL) and heatuntil the solid dissolves. Combine (E)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (372.6mg, 0.86 mmol) and warm ethanol (3 mL) and add with stirring to thecitric acid solution prepared above. Cool to 4° C. and allow to standfor 18 hours. Filter to give the title compound as a solid: mp;127°-130° C.

EXAMPLE 4.1

(E)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt

Combine (E and Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt (0.45 mol) and tetrahydrofuran (2 L). Heat to reflux.After 1 hour, cool to ambient temperature to give a solid. Collect thesolid by filtration, rinse with tetrahydrofuran, and dry. Combine thesolid and tetrahydrofuran (420 mL) and heat to reflux. After 24 hours,filter the mixture while hot, rinse with tetrahydrofuran, and dry togive (E)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt: mp; 188°-190° C.

Combine (E)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt (138.4 g, 0.294 mol) and dichloromethane. Add withstirring a solution of sodium hydroxide (12.8 g) in water (100 mL).After 30 minutes, separate the layers and extract the aqueous layer withdichloromethane. Dry the combined organic layers over MgSO₄, filter, andevaporate in vacuo to give a residue. Combine the residue and acetone (1L). Filter and combine the filtrate with a solution of citric acid (56.5g, 0.294 mol) in acetone (2 L). Allow to stand at ambient temperature togive a solid. Collect the solid by filtration, rinse with acetone, anddry to give the title compound as a solid: mp; 133°-135° C.

EXAMPLE 4.2

(E)-1- 4-(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt

Combine (E and Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt (21.5 mol) and tetrahydrofuran (75 L). Heat toreflux. After 1 hour, cool to 30° C. to give a solid. Collect the solidby filtration, rinse with tetrahydrofuran, and dry. Combine the solidwith tetrahydrofuran (83.2 L) and heat to reflux. After 18 hour, cool to50° C. and filter, rinse with tetrahydrofuran, and dry to give (E)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt.

Combine (E)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt (138.4 g, 0.294 mol) and ethyl acetate (75 L). Addwith stirring a solution of sodium hydroxide (3.0 kg, 75 mol) in water(20 L). After dissolution, separate the layers, dry the organic layerover MgSO₄, filter, and evaporate in vacuo to give a residue. Combinethe residue and acetone (80 L). Filter and combine the filtrate with asolution of citric acid (3.6 kg, 18.8 mol) in acetone (20 L) and stir togive a solid. After 18 hours, collect the solid by filtration, rinsewith acetone, and dry to give the title compound as a solid. ElementalAnalysis calculated for C₂₈ H₃₂ ClNO.C₆ H₈ O₇ : C, 65.22; H, 6.44; N,2.24. Found: C, 65.19; H, 6.29; N, 2.14.

EXAMPLE 5

(Z)-1- 4(4-Diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR15##

Combine citric acid (167.6 mg, 0.87 mmol) and ethanol (3 mL) and heatuntil the solid dissolves. Combine (Z)-1-4-(4-diethylaminobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (378.7mg, 0.87 mmol) and warm ethanol (3 mL) and add with stirring to thecitric acid solution prepared above. Cool to 4° C. and allow to standfor 18 hours. Filter to give the title compound as a solid: mp;150°-151° C.

EXAMPLE 6

(E and Z)-1-4-(4-Ethylaminobutoxy)phenyl-1,2-diphenyl!-2-chloro-ethylene citratesalt ##STR16##

Combine (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (1.0 g, 2.5mmol), ethylamine (15 mL, 193 mmol), potassium iodide (0.200 g), ethanol(2 mL), and water (5 mL). Heat to a gentle reflux. After 24 hours, coolto ambient temperature and concentrate in vacuo to obtain a residue.Chromatograph on silica gel eluting with 7% methanol/dichloromethane toobtain a residue. Combine the residue and butanone (6 mL). Add citricacid (0.52 g, 2.7 mmol) dissolved in butanone (4 mL). Allow to slowlyevaporate until a solid forms, filter, and dry in vacuo to give thetitle compound.

EXAMPLE 7

(E and Z)-1- 4-(4-(Piperidin-1-yl)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR17##

Combine (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (1.0 g, 2.5mmol), piperidine (7.5 g), potassium iodide (0.200 g) and water (5 mL).Heat to 80° C. After 18 hours, cool to ambient temperature and partitionthe reaction mixture between water and ethyl acetate. Separate theorganic layer and extract 3 times with water. Dry the organic layer overMgSO₄ and evaporate in vacuo. Chromatograph on silica gel eluting with6% methanol/dichloromethane to obtain a residue (1.01 g). Combine theresidue and butanone (6 mL). Add citric acid (0.423 g, 2.2 mmol)dissolved in butanone (2 mL). Evaporate in vacuo to give the titlecompound.

EXAMPLE 8

(E and Z)-1- 4-4-(4-Methylpiperazin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR18##

Combine (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (1.0 g, 2.5mmol), 4-methylpiperazine (5 mL), potassium iodide (0.200 g), and water(3 mL). Heat to 80° C. After 18 hours, cool to ambient temperature andpartition the reaction mixture between water and ethyl acetate. Separatethe organic layer and extract 3 times with water. Dry the organic layerover MgSO₄ and evaporate in vacuo. Chromatograph on silica gel elutingwith 5% methanol/dichloromethane to obtain a residue (0.758 g). Combinethe residue and butanone (4 mL). Add citric acid (0.307 g, 1.6 mmol)dissolved in butanone (2 mL). Allow to slowly evaporate until a solidforms, filter, and dry in vacuo to give the title compound.

EXAMPLE 9

(E and Z)-1-4-(4-(Pyrrolidin-1-yl)-butoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR19##

Combine (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.9 g, 2.25mmol), pyrrolidine (5 mL), potassium iodide (0.200 g), and water (5 mL).Heat to 80° C. After 18 hours, cool to ambient temperature and partitionthe reaction mixture between water and ethyl acetate. Separate theorganic layer and extract 3 times with water. Dry the organic layer overMgSO₄ and evaporate in vacuo. Chromatograph on silica gel eluting with6% methanol/dichloromethane to obtain a residue (0.499 g). Combine theresidue and butanone (2 mL). Add citric acid (0.211 g, 1.1 mmol)dissolved in butanone (2 mL). Allow to slowly evaporate until a solidforms, filter, and dry in vacuo to give the title compound.

EXAMPLE 10

(E and Z)-1- 4-(5-Chloropentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1- (4-hydroxy)phenyl!-1,2-diphenyl-2-chloro-ethylene(2.3 g, 7.5 mmol) and 5-bromo-1-chloropentane (2.78 g, 15.0 mmol) inethanol (40 mL). Add a solution of sodium ethoxide in ethanol (11.12 mL,0.67M, 7.5 mmol). Heat to reflux under an inert atmosphere. After 24hours concentrate in vacuo. Chromatograph on silica gel eluting with 1/7ethyl acetate/hexane. Concentration of the product containing fractionsto give the title compound which is taken on to the next step withoutfurther purification.

EXAMPLE 11

(E and Z)-1-4-(5-Diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1-4-(5-chloropentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (3.08 g, 7.5mmol), diethylamine (5.5 g, 75.0 mmol) and potassium iodide (30 mg,0.178 mmol) in water (8.0 mL). Heat to 40° C. for 4 hours and then coolto ambient temperature and allow to stand for 72 hours. Add diethylamine(10 mL) and heat to 80° C. After 3 hours chromatograph on silica geleluting first with 20% ethyl acetate/hexane and then with 20% ethylacetate/hexane containing 5% triethylamine. Combine product containingfractions and concentrate in vacuo. Chromatograph, again, on silica geleluting with 7% methanol/dichloromethane. Concentration of productcontaining fractions to give a mixture of the isomers as a residue.Separate the isomers by HPLC, 90 mg per injection, using a Waters andAssociates μPorasil column (19 mm by 300 mm), eluting with 80/20/0.2chloroform/hexane/triethylamine at 20 mL/minute to give (E)-1-4-(5-diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1- 4-(5-diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 12

(E)-1- 4-(5-Diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR20##

Combine citric acid (192.13 mg, 1.21 mmol) and isopropanol (3 mL) andheat until the solid dissolves. Combine (E)-1-4-(5-diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (543.2mg, 1.21 mmol) and warm isopropanol (3 mL) and add with stirring to thecitric acid solution prepared above. Filter while still warm and thencool in a freezer at -20° C. until crystals begin to form and then allowto stand at ambient temperature for 18 hours. Filter to give the titlecompound as a solid: mp; 124°-127° C.

EXAMPLE 13

(Z)-1- 4-(5-Diethylaminopentoxy)phenyl!-1,2-diphenyl!-2-chloro-ethylenecitrate salt ##STR21##

Combine citric acid (192.13 mg, 1.21 mmol) and isopropanol (3 mL) andheat until the solid dissolves. Combine (Z)-1-4-(5-diethylaminopentoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (543.2mg, 1.21 mmol) and warm isopropanol (3 mL) and add with stirring to thecitric acid solution prepared above. Filter while still warm and thencool in a freezer at -20° C. until crystals begin to form and then allowto stand at ambient temperature for 18 hours. Filter to give the titlecompound as a solid: mp; 124°-127° C.

EXAMPLE 14

1,1-Bis-(4-methoxy)phenyl-2-phenyl-ethanol

Combine benzylmagnesium chloride (180 mL, 2M in tetrahydrofuran, 360mmol) and 4,4'-dimethoxybenzophenone (50 g, 207 mmol), Heat to a gentlereflux. After 72 hours, carefully pour the reaction mixture onto amixture of ice (300 g) and a saturated aqueous solution of ammoniumchloride (50 mL). Extract with diethyl ether, dry the organic layer overMgSO₄, and evaporate in vacuo to give the title compound.

EXAMPLE 15

1,1-Bis-(4-methoxy)phenyl-2-phenyl-ethylene

Combine 1,1-bis-(4-methoxy)phenyl-2-phenyl-ethanol obtained in Example14 and 12M hydrochloric acid (50 mL) is ethanol (400 mL). Heat toreflux. After 24 hours, cool the reaction mixture to ambienttemperature. Evaporate in vacuo to obtain a reside. Partition theresidue between water and ethyl acetate. Separate the organic layer, dryover the MgSO₄, and evaporate in vacuo to give the title compound.

EXAMPLE 16

1,1-Bis-(4-methoxy)phenyl-2-phenyl-2-chloro-ethylene

Combine 1,1-bis-(4-methoxy)phenyl-2-phenyl-ethylene (24 g, 75.8 mmol)and N-chlorosuccinimide (10.7 g, 80 mmol) in chloroform (100 mL). Heatto 60° C. After 18 hours, cool to ambient temperature and evaporate invacuo. Chromatograph on silica gel eluting with 1/10 ethylacetate/hexane to give the title compound.

EXAMPLE 17

1,1-Bis-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene

Heat pyridinium hydrochloride (140 g, 1210 mmol) to 220° C. Addportionwise, 1,1-bis-(4-methoxy)phenyl-2-phenyl-2-chloro-ethylene (37.5g, 107 mmol) and maintain the temperature at 220° C. After 45 minutes,pour the reaction mixture onto ice (400 g). Extract with ethyl acetate.The organic layer is extracted with water and 0.5M hydrochloric acidsolution. Separate the organic layer, dry over the MgSO₄, and evaporatein vacuo to give the title compound.

EXAMPLE 18

(E and Z)-1-4-(4-Chlorobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethyleneand 1,1-Bis- 4-(4-chlorobutoxy)phenyl!-2-phenyl-2-chloro-ethylene

Add sodium metal (0.440 g, 19 mmol) and ethanol (80 mL) and stir untilthe sodium metal has reacted. Add1,1-bis-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene (5.56 g, 17.2 mmol)and heat the reaction mixture to 40° C. for 15 minutes. Add1-bromo-4-chlorobutane (0.34 g, 20 mmol) and heat to a gentle reflux.After 72 hours, evaporate in vacuo. Chromatograph on silica gel elutingwith dichloromethane to give (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene(2.5 g) and 1,1-bis-4-(4-chlorobutoxy)phenyl!-2-phenyl-2-chloro-ethylene (0.96 g).

EXAMPLE 19

(E and Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene

Combine (E and Z)-1-4-(4-chlorobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene(2.5 g, 6 mmol), diethylamine (50 mL), potassium iodide (0.50 g), andwater (50 mL). Heat to a gentle reflux. After 16 hours, cool thereaction mixture to ambient temperature. Partition the reaction mixturebetween water and ethyl acetate. Separate the organic layer, dry overMgSO₄, and evaporate in vacuo. Chromatograph on silica gel eluting with15% methanol/dichloromethane to give a residue. Combine the residue andchloroform (50 mL). Divide the chloroform solution in half. Evaporateone half in vacuo to obtain a residue. Combine the residue obtained fromthe chloroform solution and butanone (7 mL). Add citric acid (0.345 g)dissolved in butanone (4 mL) and methanol (1 mL). Allow to stand until asolid forms, collect by filtration and dry in vacuo to give the titlecompound. Evaporate one half in vacuo to obtain a residue for separationof the isomers on HPLC. Separate the isomers by HPLC, 20 mg perinjection, using a 5 μm Spherisorb CN (column #61037) (21.2 mm by 250mm), eluting with 55/40/5 chloroform/hexane/methanol containing 0.05%triethylamine at 20 mL/minute to give (E)-1-4-(4-diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethyleneand (Z)-1-4-(4-diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene.

EXAMPLE 19.1

(E and Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene

Combine 4,4'dihydroxybenzophenone (21.4 g, 0.10 mmol) and sodiumhydroxide (4.0 g, 0.10 mmol) in water (50 mL). Heat to 80° C. Addtoluene (100 mL). Add benzyl chloride (17.3 mL, 0.15 mmol) intoluene/methanol (100 mL/40 mL). Maintain heating at 70° C. to 80° C.After 3 days, cool to ambient temperature and partition the reactionmixture between ethyl acetate and water. Separate the layers and extractthe aqueous layer with ethyl acetate. Combine the organic layers andextract with aqueous 1M sodium hydroxide solution and then water.Evaporate the organic layers in vacuo to give a reside. Combine theaqueous layers and allow to stand to give a solid. Collect the solid byfiltration, rinse with water, and dry to give a solid. Combine the solidand the residue obtained from evaporation of the organic layers andrecrystallize from toluene to give 4-benzyloxy-4'-hydroxybenzophenone:R_(f) =0.21 (silica gel, 30% ethyl acetate/hexane).

Combine 4-benzyloxy-4'-hydroxybenzophenone (9.12 g, 30.0 mmol) andsodium hydroxide (1.8 g, 45 mmol) in water (35 mL). Addtetrabutylammonium hydrogensulfate (1.02 g, 3.0 mmol). Add1-bromo-4-chlorobutane (5.2 mL, 45 mmol). Heat to reflux. After 3 hours,cool the reaction mixture to give a solid. Collect the solid byfiltration, rinse with water, and dry to give4-benzyloxy-4'-(4-chlorobutyloxy)benzophenone: R_(f) =0.32 (silica gel,30% ethyl acetate/hexane).

Combine 4-benzyloxy-4'-(4-chlorobutyloxy)benzophenone (3.95 g, 10.0mmol) and tetrahydrofuran (50 mL). Add a solution benzylmagnesiumchloride (6.0 mL, 2M in tetrahydrofuran, 12 mmol). After 1 hour, cool to0° C. and add a saturated aqueous solution of ammonium chloride and stirfor 1 hour to give a solid. Filter the solid and rinse three times withtetrahydrofuran. Combine the filtrate and rinses and separate thelayers. Extract the organic layer with a saturated sodium chloridesolution. Dry the organic layer over MgSO₄, filter, and dry in vacuo togive a 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenylethanol: R_(f) =0.36 (silica gel, 30% ethyl acetate/hexane).

Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenylethanol (1.0 g, 21.0 mmol) and methanol (2 mL). Add aqueous 2Mhydrochloric acid solution (4 mL). Heat to reflux. After 2 hours,concentrate at 65° C. to remove most of the methanol. Cool to ambienttemperature and extract with dichloromethane. Dry the organic layer overMgSO₄, filter, and dry in vacuo to give1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethylene:R_(f) =0.50 (silica gel, 30% ethyl acetate/hexane).

Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-phenylethylene (3.5 g, 7.5 mmol) and chloroform 935 mL). AddN-chlorosuccinimide (1.99 g, 14.9 mmol). Heat at reflux. After 18 hours,cool the reaction mixture and extract with water, aqueous saturatedsodium bicarbonate solution and water. Dry the organic layer over MgSO₄,filter, and dry in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 10% ethyl acetate/hexane to give1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenylethylene.

Combine1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenylethylene (0.1 g, 0.20 mmol), 5% palladium-on-carbon (30 mg), and ethylacetate (1.5 mL). Treat with hydrogen at atmospheric pressure. After 1.5hours, filter using a 0.45 micron membrane. Concentrate the filtrate invacuo to give1-(4-hydroxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenylethylene.

Combine with diethylamine by the method of Example 19 to give the titlecompound.

EXAMPLE 20

(E)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylenecitrate salt ##STR22##

Combine citric acid (48 mg, 0.25 mmol) and butanone (10 mL). Combine(E)-1-4-(4-diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene(115 mg, 0.26 mmol). Allow to stand until a solid forms, filter to givethe title compound as a solid: mp; 94°-96° C.

EXAMPLE 21

(Z)-1-4-(4-Diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylenecitrate salt ##STR23##

Combine citric acid (48 mg, 0.25 mmol) and butanone (10 mL). Combine(E)-1-4-(4-diethylaminobutoxy)phenyl!-1-(4-hydroxy)phenyl-2-phenyl-2-chloro-ethylene(118 mg, 0.26 mmol). Allow to stand until a solid forms, filter to givethe title compound as a solid: mp; 90°-92° C.

EXAMPLE 22

1,1-Bis- 4-(4-diethylaminobutoxy)phenyl!-2-phenyl-2-chloro-ethylene##STR24##

Combine 1,1-bis- 4-(4-chlorobutoxy)phenyl!-2-phenyl-2-chloro-ethylene(0.950 g, 1.89 mmol), diethylamine (15 mL), potassium iodide (0.10 g),ethanol (5 mL), and water (15 mL). Heat to a gentle reflux. After 8hours, cool the reaction mixture to ambient temperature. Partition thereaction mixture between water and ethyl acetate. Separate the organiclayer, dry over the MgSO₄, and evaporate in vacuo. Chromatograph onsilica gel eluting with 20% methanol/dichloromethane to give a residue.Combine the residue and butanone (5 mL). Add citric acid (0.110 g)dissolved in butanone (5 mL). Heat and add methanol until dissolution.Allow to slowly evaporate until a solid forms, collect by filtration anddry in vacuo to give the title compound.

EXAMPLE 23

4-(4-Bromobutoxy)benzophenone

Combine 4-hydroxybenzophenone (14.11 g, 71.2 mmol) and aqueous 1M sodiumhydroxide solution (70 mL). Add 1,4-dibromobutane (43.4 g, 200 mmol).Heat the reaction mixture to reflux. After 20.5 hours, cool to ambienttemperature. Add pentane (100 mL) and again heat to reflux. After 0.5hours, cool to ambient temperature to give a solid. Collect the solid byfiltration recrystallize the solid from ethanol to give the titlecompound: mp; 42°-43° C.

EXAMPLE 24

1-(4-Bromobutoxy)phenyl-1-phenyl-2-(3-methoxyphenyl)-ethanol

Combine magnesium turnings (5.8 g, 240 mmol) and diethyl ether (35 mL).Heat to reflux. Add about 5 mL of a solution of 3-methoxybenzyl chloride(6.5 g, 41 mmol) in diethyl ether (50 mL) along with one small iodinecrystal. After the reaction starts, slowly add over about 2.5 hours, theremainder of the solution of 3-methoxybenzyl chloride. After theaddition is complete continue to heat at a gentle reflux. After 14hours, cool to ambient temperature and add to a solution of4-(4-bromobutoxy)benzophenone (12.5 g, 37.6 mmol) in tetrahydrofuran(100 mL). After 7 hours, carefully pour the reaction mixture into asaturated aqueous solution of ammonium chloride (50 mL). Extract withethyl acetate, dry the organic layer over MgSO₄, and evaporate in vacuoto give a residue. Chromatograph the residue on silica gel eluting with10% ethyl acetate/hexane to give the title compound.

EXAMPLE 25

(E and Z)-1-(4-Bromobutoxy)phenyl-1-phenyl-2-(3-methoxyphenyl)-ethylene

Combine 1-(4-bromobutoxy)phenyl-1-phenyl-2-(3-methoxyphenyl)-ethanol(7.2 g, 15.7 mmol) and dichloromethane (100 mL). Add trifluoroaceticanhydride (5 mL, 35 mmol). Heat to reflux. After 21 hours, cool thereaction mixture to ambient temperature. Evaporate in vacuo to obtain areside. Partition the residue between water and ethyl acetate. Separatethe organic layer, extract with aqueous sodium bicarbonate solution, dryover the MgSO₄, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 10% ethyl acetate/hexane to givethe title compound.

EXAMPLE 26

(E andZ)-1-(4-Bromobutoxy)phenyl-1-phenyl-2-(3-methoxyphenyl)-2-chloro-ethylene

Combine (E andZ)-1-(4-bromobutoxy)phenyl-1-phenyl-2-(3-methoxyphenyl)-ethylene (0.15g, 0.34 mmol) and N-chlorosuccinimide (0.11 g, 0.8 mmol) inchlorobenzene (4 mL). Heat to reflux. After 67 hours, cool to ambienttemperature and pour the reaction into diethyl ether. Extract theorganic layer with aqueous 1M sodium hydroxide solution. Dry the organiclayer over the MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 20% ethylacetate/hexane to give the title compound.

EXAMPLE 27

(E andZ)-1-(4-Iodobutoxy)phenyl-1-phenyl-2-(3-trimethylsiloxyphenyl)-2-chloro-ethylene

Combine (E andZ)-1-(4-bromobutoxy)phenyl-1-phenyl-2-(3-methoxyphenyl)-2-chloro-ethylene(0.26 g, 0.56 mmol). pyridine (0.04 g, 0.62 mmol), and chloroform (4.0mL). Add trimethylsilyl iodide (0.49 g, 2.5 mmol). After 19 hours, heatthe reaction mixture to reflux. After 2 hours, add an additional portionof trimethylsilyl iodide (1.4 g, 7.0 mmol). After 67 hours, cool thereaction mixture to ambient temperature and evaporate in vacuo to givethe title compound.

EXAMPLE 28

(E andZ)-1-(4-Diethylaminobutoxy)phenyl-1-phenyl-2-(3-hydroxyphenyl)-2-chloro-ethylene##STR25##

Combine (E andZ)-1-(4-iodobutoxy)phenyl-1-phenyl-2-(3-trimethylsiloxyphenyl)-2-chloro-ethyleneprepared in Example 27 and diethyl amine (10 mL, 96 mmol). Heat toreflux. After 18 hours, evaporate in vacuo to give a residue. Combinethe residue and ethyl acetate. Extract with water. Extract two timeswith aqueous 1M hydrochloric acid solution. Combine the acid layers andextract with diethyl ether. Neutralize the acid extract with aqueous 1Msodium hydroxide solution and extract twice with ethyl acetate. Combinethe ethyl acetate layers, dry over MgSO₄, filter, and evaporate in vacuoto give a residue. Chromatograph the residue on silica gel to give thetitle compound.

Alternately, the compounds of Formula I and Formula II in which Y is Ocan be prepared as described in Scheme B. All substituents, unlessotherwise indicated, are previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.##STR26##

In Scheme B, step a, an appropriate ω-aminoalcohol is added by aMitsunobu addition to an appropriate triaryl-ethylene of structure 1 inwhich R₈ is hydrogen to give a ω-aminoalkoxy-triaryl-ethylene ofstructure 8.

An appropriate ω-aminoalcohol, HO--(CH₂)_(m) --A, is one in which A andm are as desired in the final product of Formula I and Formula II. Anappropriate triaryl-ethylene of the structure 1 is one in which R₈ ishydrogen; R₆ is as defined for R₂, or R₆ is a suitably protected hydroxywhich after deprotection provide compounds of Formula I and Formula IIin which R₂ is a hydroxy group; and R₇ is as defined for R₃, or R₇ is asuitably protected hydroxy which after deprotection provide compounds ofFormula I and Formula II in which R₃ is a hydroxy group, or provides anintermediate for the preparation of a compound of Formula I and FormulaII in which R₃ is --O(CH₂)_(p) A₁ wherein p=m and A=A₁ ; or R₇ is asuitably protected hydroxy which allows for removal in a sequentialmanner providing an intermediate for the preparation of compounds ofFormula I and Formula II in which R₃ is --O(CH₂)_(p) A₁ wherein p≠m andeither A=A₁ or A≠A₁, or in which R₃ is --O(CH₂)_(p) A₁ wherein p=m andA≠A₁. The selection, use, removal, and sequential removal of suitablehydroxy protecting groups, such as benzyl, p-methoxybenzyl, methyl,t-butyldimethylsilyl, and acetyl, is well known and appreciated in theart and described in Protecting Groups in Organic Synthesis by T.Greene.

For example, an appropriate ω-aminoalcohol is contacted with a molarequivalent of a triaryl-ethylene of structure 1 in which R₈ is hydrogenand a molar equivalent of triphenylphosphine in a suitable solvent, suchas tetrahydrofuran (THF). Diethyl azodicarboxylate neat or as a solutionin a suitable solvent, such as tetrahydrofuran is added. After stirringfor from 1-72 hours the product can be isolated and purified bytechniques well known in the art. For the preparation of compounds ofFormula I and Formula II in which R₃ is --O(CH₂)_(p) A₁ wherein p=m andA=A₁ a compound in which R₇ is hydroxy is used along with an additionalequivalent of an appropriate ω-aminoalcohol, triphenylphosphine, anddiethyl azodicarboxylate are used. The reaction mixture can beconcentrated in vacuo to give a residue. The residue can bechromatographed on silica gel using a suitable organic eluent. Thematerial obtained from chromatography can be recrystallized to give aω-aminoalkoxy-triaryl-ethylene of structure 8.

In Scheme B, step b, a ω-aminoalkoxy-triaryl-ethylene of structure 8 ischlorinated or brominated to give a ω-aminoalkoxy-triaryl-ethylene ofstructure 4.

For example, a ω-aminoalkoxy-triaryl-ethylene of structure 8 iscontacted with a molar excess of chlorine, bromine, N-chlorosuccinimide,or N-bromosuccinimide in a suitable solvent, such as chloroform ordichloromethane. The reaction is carried out at temperatures fromambient temperature to the reflux temperature of the solvent. Afterstirring for from 12-72 hours the product can be isolated and purifiedby techniques well known in the art. For example, the reaction mixturecan be concentrated in vacuo and the product purified by techniques wellknown in the art, such as salt formation, chromatography eluting with asuitable solvent, or recrystallization from a suitable organic solvent.

In Scheme B, steps a and b, can be carried out in any order.

In Scheme B, Optional step c, for a ω-aminoalkoxy-triaryl-ethylene ofstructure 4 in which R₆ or R₇ are a protected hydroxy group theprotecting group is removed in a deprotection step to provide aω-aminoalkoxy-triaryl-ethylene of structure 5 in which either, R₂ or R₃,or R₂ and R₃, are hydroxy as desired in the final product of Formula Iand Formula II. The production of a compound of Formula I and II inwhich R₃ is --O(CH₂)_(p) A₁ wherein p≠m and either A=A₁ or A≠A₁ or inwhich R₃ is --O(CH₂)_(p) A₁ wherein p=m and either A=A₁ or A≠A₁ mayrequire the removal of protecting groups in a sequential manner toprovide a compound of the structure 4 in which R₇ is a hydroxy group. Asis apparent to one skilled in the art a compound of the structure 4 inwhich R₇ is a hydroxy group can be subjected to steps b and c of SchemeA or step a of Scheme B to give a bis-ω-aminoalkoxy-triaryl-ethylenecompound of Formula I and II in which R₃ is --O(CH₂)_(p) A₁ wherein p≠mand either A=A₁ or A≠A₁ or in which R₃ is --O(CH₂)_(p) A₁ wherein p=mand A≠A₁ or a bis-ω-aminoalkoxy-triaryl-ethylene compound of Formula Iand II wherein p=m and A=A₁.

The selection, use, removal, and sequential removal of suitable hydroxyprotecting groups, such as benzyl, p-methoxybenzyl, methyl,t-butyldimethylsilyl, and acetyl, is well known and appreciated in theart and described in Protecting Groups in Organic Synthesis by T.Greene.

In Scheme B step d, the isomers of a ω-aminoalkoxy-triaryl-ethylene ofstructure 4 or 5 are separated to give the(E)-ω-aminoalkoxy-triaryl-ethylene and the(Z)-ω-aminoalkoxy-triaryl-ethylene as taught in Scheme A step e.

Pharmaceutically acceptable salts of a(E)-ω-aminoalkoxy-triaryl-ethylene or a(Z)-ω-aminoalkoxy-triaryl-ethylene can be formed in an additional stepas is well known and practiced in the art.

The following examples present typical syntheses as described in SchemeB. These examples are understood to be illustrative only and are notintended to limit the scope of the invention in any way. As used in thefollowing examples, the following terms have the meanings indicated: "g"refers to grams, "mg" refers to milligrams, "mmol" refers to millimoles,"mL" refers to milliliters, "°C." refers to degrees Celsius, "mp" refersto melting point, "HPLC" refers to high performance liquidchromatography.

EXAMPLE 29

(E and Z)-1- 4-(6-Diethylaminohexoxy)phenyl!-12-diphenyl-ethylene

Combine (E and Z)-1- (4-hydroxy))phenyl!-1,2-diphenyl-ethylene (3.05 g,11.2 mmol), 6-diethylaminohexanol (2.0 g, 11.5 mmol), andtriphenylphosphine (3.73 g, 14.2 mmol) in THF (25 mL). Add dropwisediethyl azodicarboxylate (2.24 mL, 14.2 mmol). Stir for 24 hours.Concentrate in vacuo. Chromatograph on silica gel eluting with 7%methanol/dichloromethane. Concentration of the product containingfractions to give the title compound.

EXAMPLE 30

(E and Z)-1-4-(6-Diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1-4-(6-diethylaminohexoxy)phenyl!-1,2-diphenyl-ethylene (2.17 g, 5.07mmol), N-chlorosuccinimide (0.745 g, 5.57 mmol), and chloroform (40 mL).Heat to reflux for 18 hours. Cool to ambient temperature. AddN-chlorosuccinimide (0.745 g, 5.57 mmol). Heat to reflux. After 2 hoursevaporate in vacuo. Chromatograph on silica gel eluting with 10%methanol/dichloromethane. Combine product containing fractions andconcentrate in vacuo to give the title compound. Separate the isomers byHPLC, 90 mg per injection, using a Waters and Associates μPorasil column(19 mm by 300 mm), eluting with 80/20/0.2chloroform/hexane/triethylamine at 20 mL/minute to give (E)-1-4-(6-diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1- 4-(6-diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 31

(E)-1- 4-(6-Diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR27##

Combine citric acid (370 mg, 0.80 mmol) and ethanol (4 mL) and heatuntil the solid dissolves. Combine (E)-1-4-(6-diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (154 mg,0.80 mmol) and warm ethanol (5 mL) and add with stirring to the citricacid solution prepared above. Filter while still warm and then cool in afreezer at -20° C. until crystals begin to form and then allow to standat ambient temperature for 18 hours. Filter to give the title compoundas a solid: mp; 84°-87° C.

EXAMPLE 32

(Z)-1- 4-(6-Diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR28##

Combine citric acid (56 mg, 0.29 mmol) and ethanol (2 mL) and heat untilthe solid dissolves. Combine (Z)-1-4-(6-diethylaminohexoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (134 mg,0.29 mmol) and warm ethanol (3 mL) and add with stirring to the citricacid solution prepared above. Filter while still warm and then cool in afreezer at -20° C. until crystals begin to form and then allow to standat ambient temperature for 18 hours. Filter to give the title compoundas a solid: mp; 84°-87° C.

EXAMPLE 33

(E and Z)-1-4-(7-Diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Prepare by the methods taught in Example 29, using7-diethylaminoheptanol, and Example 24 to give the title compound.Separate the isomers by HPLC, using multiple injections, using a Watersand Associates μProasil column (19 mm by 300 mm), eluting with19/4.8/76.2/0.1 ethyl acetate/chloroform/hexane/triethylamine at 20mL/minute to give (E)-1-4-(7-diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1- 4-(7-diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 34

(E)-1- 4-(7-Diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR29##

Combine (E)-1-4-(7-diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.225g) and hot isopropyl alcohol (4 mL). Add a solution of citric acid(0.090 g) in hot isopropyl alcohol (2 mL). Allow to cool and evaporateuntil a solid forms. Filter and dry to give the title compound: mp;106°-108° C.

EXAMPLE 35

(Z)-1- 4-(7-Diethylaminoheptoxy)phenyl)-1,2-diphenyl!-2-chloro-ethylenecitrate salt ##STR30##

Combine (Z)-1-4-(7-diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.087 g) and hot isopropyl alcohol (3 mL). Add a solution of citric acid (0.035g) in hot isopropyl alcohol (1 mL). Allow to cool and evaporate until asolid forms. Filter and dry to give the title compound: mp; 94°-96° C.

EXAMPLE 36

(E and Z)-1-4-(8-Diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Prepare by the methods taught in Example 9, using 8-diethylaminooctanol,and Example 30 to give the title compound. Separate the isomers by HPLC,using multiple injections, using a 5 μm Spherisorb CN (21.2 mm by 250mm), eluting with 50/50/chloroform/hexane containing 0.1% triethylamineat 20 mL/minute to give (E)-1-4-(7-diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1- 4-(7-diethylaminoheptoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 37

(E)-1- 4-(8-Diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR31##

The citrate salt is formed in butanone (2 mL) using (E)-1-4-(8-diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.063 g)and citric acid (0.025 g) to give the title compound: mp; 90°-92° C.

EXAMPLE 38

(Z)-1- 4-(8-Diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR32##

The citrate salt is formed in butanone (0.5 mL) using (Z)-1-4-(8-diethylaminooctoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.049 g)and citric acid (0.0094 g): mp; 105°-107° C.

EXAMPLE 39

(E and Z)-1-4-(9-Diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Prepare by the methods taught in Example 29, using 9-diethylaminonanol,and Example 30 to give the title compound. Separate the isomers by HPLC,using multiple injections, using a 5 μm Spherisorb CN (21.2 mm by 250mm), eluting with 40/60/chloroform/hexane containing 0.1% triethylamineat 20 mL/minute to give (E)-1-4-(9-diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1- 4-(9-diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 40

(E)-1- 4-(9-Diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR33##

The citrate salt is formed in butanone (2 mL) using (E)-1-4-(9-diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.105 g)and citric acid (0.040 g) in butanone (2 mL) to give the title compound:mp; 92°-3° C.

EXAMPLE 41

(Z)-1- 4-(9-Diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR34##

The citrate salt is formed in butanone (0.5 mL) using (Z)-1-4-(9-diethylaminononoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.036 g)and citric acid (0.013 g) in butanone (2 mL) to give the title compound:mp; 83°-85° C.

EXAMPLE 42

(E and Z)-1-4-(10-Diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Prepare by the methods taught in Example 29, using10-diethylaminodecanol, and Example 30 to give the title compound.Separate the isomers by HPLC using multiple injections, using a 5 μmSpherisorb CN (21.2 mm by 250 mm), eluting with 30/70/chloroform/hexanecontaining 0.1% triethylamine at 20 mL/minute to give (E)-1-4-(10-diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1- 4-(10-diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 43

(E)-1- 4-(10-Diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR35##

The citrate salt is formed in butanone (2 mL) using (E)-1-4-(10-diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.092g) and citric acid (0.034 g) in butanone (0.5 mL) to give the titlecompound: mp; 94°-95° C.

EXAMPLE 44

(Z)-1- 4-(10-Diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR36##

The citrate salt is formed in butanone (0.5 mL) using (Z)-1-4-(10-diethylaminodecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.046g) and citric acid (0.017 g) in butanone (0.5 mL) to give the titlecompound: mp; 89°-90° C.

EXAMPLE 45

(E and Z)-1-4-(11-Diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Prepare by the methods taught in Example 29, using11-diethylaminoundecanol, and Example 30 to give the title compound.Separate the isomers by HPLC using multiple injections, using aLichrosorb RP-18 column (21 mm by 250 mm), eluting with methanolcontaining 0.05% triethylamine at 20 mL/minute to give (E)-1-4-(11-diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1-4-(11-diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 46

(E)-1- 4-(11-Diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR37##

The citrate salt is formed in butanone (2 mL) using (E)-1-4-(11-diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.082g) and citric acid (0.029 g) in butanone (1 mL) to give the titlecompound: mp; 104°-105° C.

EXAMPLE 47

(Z)-1- 4-(11-Diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR38##

The citrate salt is formed in butanone (2 mL) using (Z)-1-4-(11-diethylaminoundecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene(0.0284 g) and citric acid (0.0102 g) in butanone (1 mL) to give thetitle compound: mp; 89°-92° C.

EXAMPLE 48

(E and Z)-1-4-(12-Diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene

Prepare by the methods taught in Example 29, using12-diethylaminododecanol, and Example 30. Separate the isomers by HPLCusing multiple injections, using a Lichrosorb RP-18 column (21 mm by 250mm), eluting with methanol containing 0.05% triethylamine at 20mL/minute to give (E)-1-4-(12-diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene and(Z)-1-4-(12-diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene.

EXAMPLE 49

(E)-1- 4-(12-Diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR39##

The citrate salt is formed in butanone (2 mL) using (E)-1-4-(12-diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene: mp;96°-98° C., (0.090 g) and citric acid (0.031 g) in butanone (0.5 mL) togive the title compound: mp; 96°-98° C.

EXAMPLE 50

(Z)-1- 4-(12-Diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR40##

The citrate salt is formed in butanone (2 mL) using (Z)-1-4-(12-diethylaminododecoxy)phenyl!-1,2-diphenyl-2-chloro-ethylene (0.032g) and citric acid (0.011 g) to give the title compound: mp; 98°-100° C.

The compounds of Formula I and II which Y is NH and compounds of FormulaIII and IV can be prepared as described in Scheme C. In Scheme C,compounds which include the alkylene group (CH₂)_(n) wherein n is aninteger from 2 to 12 encompass the compounds of Formula I, II, III, andIV. All substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art. ##STR41##

In Scheme C, step a, an appropriate ω-haloalkylacid halide, Z--(CH₂)_(q)--C(O)Z₁, is added to an appropriate amino-triaryl-ethylene of structure9 in an acylation reaction to give a ω-haloalkylamido-triaryl-ethyleneof structure 10.

An appropriate ω-haloalkylacid halide, Z--(CH₂)_(q) --C(O)Z₁, is one inwhich q is 1 less than n, an integer for 2 to 12 as desired in the finalproduct of Formula I, II, III, or IV, and Z and Z₁ may eachindependently be a chlorine atom or a bromine atom. An appropriateamino-triaryl-ethylene of the structure 9 is one in which R₆ is R₂ asdefined above, or is a suitably protected hydroxy which afterdeprotection provide compounds of Formula I, II, III, or IV in which R₂is a hydroxy group; R₉ is R₃ as defined above, or is a suitablyprotected hydroxy which after deprotection provide compounds of FormulaI, II, III, or IV in which R₃ is a hydroxy group, or R₉ is an aminogroup, a protected amino group, or a group which gives rise to an aminogroup, such as a nitro group. Appropriate amino-triaryl-ethylenes of thestructure 9 are readily prepared by methods analogous to those used toprepare triaryl-ethylene of structure 1 described in U.S. Pat. No.2,914,563, R. E. Allen et al; U.S. Pat. No. 2,429,556, C. F. Longfellowet al; and Syn. Comm. 17, 1787-1796 (1987), M. I. Al-Hassan.

For example, a slight molar excess of a ω-haloalkylacid halide iscontacted with a amino-triaryl-ethylene of the structure 9 in a suitablesolvent, such as pyridine, dimethylformamide, acetonitrile, ortetrahydrofuran. The reaction is carried out in the presence of asuitable base, such as pyridine, triethylamine, sodium carbonate, orsodium bicarbonate. The reaction may be carried out in the presence of acatalyst, such as 4-dimethylaminopyridine. The reaction is stirred forfrom 1-72 hours. The production of a compound of Formula I or II inwhich R₃ is --NH(CH₂)_(p) A₁ wherein p=m and A=A₁ or a compound ofFormula III or IV in which R₃ is --NH(CH₂)_(z) A₁ wherein z=w and A=A₁requires the use of a compound of structure 1 in which R₉ is amino andslightly more than two molar equivalents of a ω-haloalkylacid halide andgives rise to a compound of structure 10 which is abis-ω-haloalkylamido-triaryl-ethylene. The product can be isolated andpurified by techniques well known in the art. For example, the reactionmixture can be concentrated in vacuo to give a residue. The residue canbe chromatographed on silica gel using a suitable organic eluent. Thematerial obtained from chromatography can be recrystallized to give aω-haloalkylamido-triaryl-ethylene of structure 10.

In Scheme C, step b, a ω-haloalkylamido-triaryl-ethylene of structure 10is contacted in an amination reaction with an appropriate amine, HNRR₁,in which R and R₁ are as defined above, morpholine, piperidine,piperazine, 4-methylpiparizine, or pyrrolidine to giveω-aminoalkylamido-triaryl-ethylene of structure 11.

For example, a ω-haloalkylamido-triaryl-ethylene of structure 10 iscontacted with a large molar excess of an appropriate amine. A largemolar excess of amine is used so that the amine also acts as a base totake up the acid liberated in the reaction. The reaction is carried outin a suitable solvent, such as ethanol, methanol, water, ethanol/watermixtures, or methanol/water mixtures. The reaction may be carried out inthe presence of a suitable catalyst, such as potassium iodide. Thereaction vessel may be sealed to prevent the escape of volatile amines.The reaction mixture is heated to temperatures of from 40° C. to 100° C.For compounds of structure 10 in which R₉ is a ω-haloalkylamido groupthe use of an additional portion of an appropriate amine gives abis-ω-aminoalkylamido-triaryl-ethylene which gives rise to a compound ofFormula I or II in which R₃ is --NH(CH₂)_(p) A₁ wherein p=m and A=A₁ ora compound of Formula III or IV in which R₃ is --NH(CH₂)_(z) A₁ whereinz=w and A=A₁ The product is isolated from the reaction zone byevaporation or extraction and is purified by chromatography or saltformation and recrystallization to give aω-aminoalkylamido-triaryl-ethylene of structure 11.

In Scheme C, step c, a ω-aminoalkylamido-triaryl-ethylene of structure11 are chlorinated or brominated to giveω-aminoalkylamido-triaryl-ethylene of structure 12.

For example, a ω-aminoalkylamido-triaryl-ethylene of structure 11 iscontacted with a molar excess of chlorine, bromine, N-chlorosuccinimide,or N-bromosuccinimide in a solvent, such as chloroform ordichloromethane. The reaction is carried out at temperatures fromambient temperature to the reflux temperature of the solvent. Afterstirring for from 12-72 hours the product can be isolated and purifiedby techniques well known in the art. For example, the reaction mixturecan be concentrated in vacuo and the product purified by chromatographyor by recrystallization to give a ω-aminoalkylamido-triaryl-ethylene ofstructure 12.

In Scheme C, step d, a ω-aminoalkylamido-triaryl-ethylene of structure12 is contacted with an appropriate reducing agent in a reductionreaction to give a ω-aminoalkylamino-triaryl-ethylene of structure 13.

An appropriate reducing agent is one that will reduce the amido group ofa ω-aminoalkylamido-triaryl-ethylene of structure 12 without effectingthe other groups present in the compound. The selection and use of suchreducing agents is well known and appreciated in the art.

For example, a ω-aminoalkylamido-triaryl-ethylene of structure 12 iscontacted with a molar excess of an appropriate reducing agent, such aslithium aluminum hydride, borane, or borane complexes. The reaction iscarried out in a solvent, such as diethyl ether or tetrahydrofuran whenthe appropriate reducing agent is lithium aluminum hydride, ordichloromethane or chloroform when the appropriate reducing agent isborane. The reaction is carried out at temperatures from ambienttemperature to the refluxing temperature of the solvent. For compoundsof structure 12 in which R₉ is a ω-aminoalkylamido group the use of anadditional portion of the appropriate reducing agent gives abis-ω-aminoalkylamino-triaryl-ethylene which gives rise to a compound ofFormula I or II in which R₃ is --NH(CH₂)_(p) A₁ wherein p=m and A=A₁ ora compound of Formula III or IV in which R₃ is --NH(CH₂)_(z) A₁ whereinz=w and A=A₁. The product can be isolated from the reaction zone bytechniques well known in the art, such as quenching, extraction, andevaporation; and may be purified by methods well known in the art, suchas chromatography and recrystallization to give aω-aminoalkylamino-triaryl-ethylene of structure 13.

In Scheme C, optional step e, for ω-aminoalkylamino-triaryl-ethylene ofstructure 13 in which R₆ or R₉ are a protected hydroxy group theprotecting group is removed in a deprotection step to provideω-aminoalkylamino-triaryl-ethylene of structure 14 in which either, R₂or R₃, or R₂ and R₃, are hydroxy as desired in the final product ofFormula I or Formula II. Additionally, forω-aminoalkylamino-triaryl-ethylene of structure 13 in which R₉ is aprotected amino group is deprotected to provideω-aminoalkylamino-triaryl-ethylene of structure 14 in which R₉ is anamino group can be, by sequentially performing the steps of Scheme C,used as an intermediate for the preparation of a compound of Formula Ior II in which R₃ is --NH(CH₂)_(p) A₁ wherein p≠n and either A=A₁ orA≠A₁ or in which R₃ is --NH(CH₂)_(p) A₁ wherein p=m and A≠A₁ or acompound of Formula III or IV in which R₃ is --NH(CH₂)_(z) A₁ whereinz≠w and either A=A₁ or A≠A₁ or in which R₃ is --NH(CH₂)_(z) A₁ whereinz=w and A≠A₁. The removal of amine protecting groups utilizing suitableprotecting groups such as those described in Protecting Groups inOrganic Synthesis by T. Greene is well known and appreciated by thoseskilled in the art.

The selection, use, removal, and sequential removal of suitable hydroxyprotecting groups, such as benzyl, p-methoxybenzyl, methyl,t-butyldimethylsilyl, and acetyl, is well known and appreciated in theart and described in Protecting Groups in Organic Synthesis by T.Greene.

In Scheme C, step f, the isomers of a ω-aminoalkylamino-triaryl-ethyleneof structure 13 or 14 are separated to give a(E)-ω-aminoalkylamino-triaryl-ethylene and the(Z)-ω-aminoalkylamino-triaryl-ethylene.

For example, the isomers of compounds of structure 13 or 14 can beseparated and purified by high-performance liquid chromatography orfractional recrystallization of salt to give a(E)-ω-aminoalkylamino-triaryl-ethylene and the(Z)-ω-aminoalkylamino-triaryl-ethylene.

Pharmaceutically acceptable salts of a(E)-ω-aminoalkylamino-triaryl-ethylene and of a(Z)-ω-aminoalkylamino-triaryl-ethylene can be formed in an additionalstep as is well known and practiced in the art.

The following examples present typical syntheses as described in SchemeC. These examples are understood to be illustrative only and are notintended to limit the scope of the invention in any way. As used in thefollowing examples, the following terms have the meanings indicated: "g"refers to grams, "mg" refers to milligrams, "mmol" refers to millimoles,"mL" refers to milliliters, "mm" refers to millimeters, "°C." refers todegrees Celsius, "R_(f) " refers to retention factor, "mp" refers tomelting point, "HPLC" refers to high performance liquid chromatography.

EXAMPLE 51

(E and Z)-1- 4-N-(4-Chlorobutyrylamino)phenyl!-1,2-diphenyl-ethylene

Combine (E and Z)-1- (4-amino)phenyl!-1,2-diphenyl-ethylene (0.57 g, 2.1mmol), 4-chlorobutyryl chloride (0.338 g, 2.4 mmol), anddimethylaminopyridine (10 mg) in pyridine (5 mL). Stir under an inertatmosphere for 16 hours. Evaporate in vacuo to give a residue. Dilutewith dichloromethane and extract 3 times with 3M hydrochloric acidsolution. Dry the organic layer over MgSO₄, filter, and evaporate invacuo to give the title compound.

EXAMPLE 52

(E and Z)-1-4-N-(4-Diethylaminobutryrylamino)phenyl!-1,2-diphenyl-ethylene

Combine (E and Z)-1-4-N-(4-chlorobutyrylamino)phenyl!-1,2-diphenyl-ethylene (3.2 g, 11.8mmol), diethylamine (30.0 mL), potassium iodide (100 mg, 0.66 mmol), andwater (2.0 mL) and seal in a pressure vessel. Heat to 100° C. for 4hours. Cool to ambient temperature and carefully open the vessel.Evaporate in vacuo. Dilute with dichloromethane and extract with water.Dry the organic layer over MgSO₄, filter, and evaporate in vacuo.Chromatograph on silica gel eluting with 10% methanol/dichloromethane.Combine product containing fractions and concentrate in vacuo to givethe title compound.

EXAMPLE 53

(E and Z)-1-4-N-(4-Diethylaminobutryrylamino)phenyl!-1,2-dipenyl-2-chloro-ethylene

Combine (E and Z)-1-4-N-(4-diethylaminobutyrylamino)phenyl!-1,2-diphenyl-ethylene (1.0 g,2.4 mmol) and N-chlorosuccinimide (0.80 g, 6.0 mmol) in dichloromethane(15 mL). Heat to reflux and stir at reflux for 48 hours. Cool to ambienttemperature. Chromatograph on silica gel eluting with 10%methanol/dichloromethane. Combine product containing fractions andconcentrate in vacuo to give the title compound.

EXAMPLE 54

(E and Z)-1-4-(4-Diethylaminobutylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene##STR42##

Combine (E and Z)-1-4-1-(4-diethylaminobutyrylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene(0.55 g, 1.23 mmol) and borane (5 mL, 1M in tetrahydrofuran, 5.0 mmol)in THF (10 mL). Heat to reflux and stir at reflux for 20 hours. Quenchwith methanol and evaporate in vacuo. Partition between dichloromethaneand water. Separate the organic layer and dry over MgSO₄, filter andevaporate in vacuo. Chromatograph on silica gel to give the titlecompound.

The compounds of Formula I and II in which Y is NH and the compounds ofFormula III and IV can also be prepared as described in Scheme D. InScheme D, compounds which include the alkylene group (CH₂)_(n) wherein nis an integer from 2 to 12 encompass the compounds of Formula I, II,III, and IV. All substituents, unless otherwise indicated, arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. ##STR43##

In Scheme D, step a, an appropriate amino-triaryl-ethylene of structure9 is acetylated to give an acetamido-triaryl-ethylene of structure 15.

An appropriate amino-triaryl-ethylene of structure 9 is as defined abovein Scheme C.

For example, an amino-triaryl-ethylene of the structure 9 is contactedwith a suitable acetyling reagent, such as acetyl chloride or aceticanhydride. The reaction is carried out in a suitable solvent, such aspyridine, dichloromethane, dimethylformamide, acetonitrile, ortetrahydrofuran. The reaction is carried out in the presence of asuitable base, such as pyridine, triethylamine, sodium carbonate, orsodium bicarbonate. The reaction is stirred for from 1-72 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, recrystallization,and trituration.

As is appreciated by one of ordinary skill in the art an alcoholprecursor to an appropriate amino-triaryl-ethylene of structure 9 can bedehydrated and acetylated in one step to give anacetamido-triaryl-ethylene of structure 15.

In Scheme D, step b, an acetamido-triaryl-ethylene of structure 15 ischlorinated or brominated as generally taught in Scheme C, step c, togive acetamido-triaryl-ethylene of structure 16.

For example, an acetamido-triaryl-ethylene of structure 15 is contactedwith a molar excess of chlorine, bromine, N-chlorosuccinimide, orN-bromosuccinimide in a solvent, such as chloroform or dichloromethane.The reaction is carried out at temperatures from ambient temperature tothe reflux temperature of the solvent. After stirring for from 12-72hours the product can be isolated and purified by techniques well knownin the art. For example, the reaction mixture can be concentrated invacuo and the product purified by chromatography or by recrystallizationto give a ω-aminoalkylamido-triaryl-ethylene of structure 12.

In Scheme D, step c, an acetamido-triaryl-ethylene of structure 16 isalkylated with an appropriate ω-aminoalkyl halide or a salt thereof togive a N-(ω-aminoalkyl)acetamido-triaryl-ethylene of structure 17.

An appropriate ω-aminoalkyl halide, A(CH₂)_(n) Z, is one in which Z is achlorine atom, a bromine atom, or a iodine atom; A and n, an integer for2 to 12 as desired in the final product of Formula I, II, III, or IV.

For example, an acetamido-triaryl-ethylene of structure 16 is contactedwith from 1.0 to 10 molar equivalents of an appropriate ω-aminoalkylhalide. The reaction is carried out in the presence of a suitable base,such as sodium ethoxide, sodium methoxide, potassium hydroxide, sodiumhydroxide, potassium hydroxide, and sodium carbonate. The reaction iscarried out in a solvent, such as ethanol, methanol, tetrahydrofuran,acetone, or butanone. The product may be isolated from the reaction zoneby evaporation and extraction and may be purified by methods well knownin the art, such as chromatography and recrystallization.

In Scheme D, step d, the acetyl group of aN-(ω-aminoalkyl)acetamido-triaryl-ethylene of structure 17 is hydrolyzedto give an ω-aminoalkylamino-triaryl-ethylene of structure 13. Thehydrolysis of acetamido compounds using either basic or acidicconditions is well known and appreciated in the art.

As generally taught in Scheme C, optional step e, anω-aminoalkylamino-triaryl-ethylene of structure 13 can be deprotectedand further modified as required to give aω-aminoalkylamino-triaryl-ethylene of structure 14.

As generally taught in Scheme C, step f, the isomers of aω-aminoalkylamino-triaryl-ethylene of structure 13 or 14 are separatedto give a (E)-ω-aminoalkylamino-triaryl-ethylene and the(Z)-ω-aminoalkylamino-triaryl-ethylene.

The following examples present typical syntheses as described in SchemeD. These examples are understood to be illustrative only and are notintended to limit the scope of the invention in any way. As used in thefollowing examples, the following terms have the meanings indicated: "g"refers to grams, "mg" refers to milligrams, "mmol" refers to millimoles,"mol" refers to moles, "mL" refers to milliliters, "mm" refers tomillimeters, "°C." refers to degrees Celsius, "R_(f) " refers toretention factor, "mp" refers to melting point, "HPLC" refers to highperformance liquid chromatography.

EXAMPLE 55

(E and Z)-1-(4-Acetamidophenyl)-1,2-diphenyl-ethylene

Combine 4-aminobenzophenone (50 g, 0.25 mol) and diethyl ether (500 mL).Slowly, add benzylmagnesium chloride (1 L of a 1M solution in diethylether over 1.5 hours. After 18 hours, pour the reaction onto ice and anaqueous solution of ammonium chloride. Separate the layers, extract theorganic layer with water, dry over MgSO₄, filter, and evaporate in vacuoto give a residue. Recrystallize from isopropanol to give1-(4-aminophenyl)-1,2-diphenyl-ethanol: mp; 105°-107° C.

Combine 1-(4-aminophenyl)-1,2-diphenyl-ethanol (40 g, 0.138 mol) andpyridine (75 mL). Slowly add acetic anhydride (50 mL). Heat on a steambath. After 20 hours, cool and evaporate in vacuo to give a residue.Partition the residue between diethyl ether and water. Separate thelayers, extract the organic layer with water, dry over MgSO₄, filter,and evaporate in vacuo to give the title compound.

EXAMPLE 56

(E and Z)-1-(4-Acetamidophenyl)-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1-(4-acetamidophenyl)-1,2-diphenyl-ethylene and aceticacid (250 mL). Slowly add chlorine (350 mL of a 0.46M solution in carbontetrachloride). After the addition, stir the reaction at ambienttemperature for 1 hour and then heat on a steam bath. After 2 hours,cool and evaporate in vacuo to give a residue. Recrystallize the residuefrom 95% ethanol to give the title compound: mp; 179°-185° C.

EXAMPLE 57

(E and Z)-1-4-(N-(2-Diethylaminoethyl)acetamidophenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1-(4-acetamidophenyl)-1,2-diphenyl-2-chloro-ethylene(17.4 g, 0.05 mol), 2-diethylaminoethyl chloride hydrochloride (10 g,0.058 mol) and powdered potassium hydroxide (6.7 g, 0.12 mol) in acetone(150 mL). Heat to reflux. After 2 hours, filter, and evaporate to give aresidue. Partition the residue between diethyl ether and water. Separatethe layers, extract the organic layer with water, dry over MgSO₄,filter, and evaporate in vacuo to give the title compound.

EXAMPLE 58

(E and Z)-1-4-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylenecitrate salt ##STR44##

Combine (E and Z)-1-4-(N-(2-diethylaminoethyl)acetamidophenyl!-1,2-diphenyl-2-chloro-ethylene,aqueous 10% hydrochloric acid (200 mL), and aqueous concentratedhydrochloric acid (10 mL). Heat on a steam bath. After 6 hours, cool toambient temperature. After 18 hours, add aqueous 10% sodium hydroxideuntil the solution becomes basic. Extract the basic solution withdiethyl ether. Extract the organic layer with water, dry over MgSO₄,filter and evaporate in vacuo to give a residue. Combine the residue andbutanone. Add citric acid (4.3 g) to give a solid. Filter andrecrystallize twice from butanone to give the title compound: mp;121°-125° C.

The compounds of Formula I and II in which Y is NH and the compounds ofFormula III and IV can be prepared as described in Scheme E. In SchemeE, compounds which include the alkylene group (CH₂)_(n) wherein n is aninteger from 2 to 12 encompass the compounds of Formula I, II, III, andIV. All substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art. ##STR45##

In Scheme E, step a, an appropriate 4-aminobenzophenone of structure 18is acetylated to give an N-acetyl-4-aminobenzophenone of structure 18a.As is appreciated by those of ordinary skill in the art groups otherthan acetyl may be used, such as trifluoroacetyl, benzoyl,methanesulfonyl, or trifluoromethanesulfonyl. An appropriate4-aminobenzophenone of structure 18 is one in which R₉ is as definedabove in Scheme C, step a.

For example, an appropriate 4-aminobenzophenone of structure 18 iscontacted with a suitable acetyling reagent, such as acetyl chloride oracetic anhydride. The reaction is carried out in a suitable solvent,such as pyridine, dichloromethane, dimethylformamide, acetonitrile,toluene, or tetrahydrofuran. The reaction is carried out in the presenceof a suitable base, such as pyridine, triethylamine, sodium carbonate,or sodium bicarbonate. The reaction is stirred for about 1-72 hours.Generally, the reaction is carried out at temperatures of from about-20° C. to the refluxing temperature of the solvent. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, chromatography, recrystallization, andtrituration.

In Scheme E, step b, the N-acetyl-4-aminobenzophenone of structure 18ais alkylated with an appropriate ω-aminoalkyl halide to give anN-ω-aminoalkyl-N-acetyl-4-aminobenzophenone of structure 19. Anappropriate ω-aminoalkyl halide, A(CH₂)_(n) Z, is one as described inScheme D, step c.

For example, a N-acetyl-4-aminobenzophenone of structure 18a iscontacted with from 1.0 to 10 molar equivalents of an appropriateω-aminoalkyl halide. The reaction is carried out in the presence of asuitable base, such as sodium ethoxide, sodium methoxide, potassiumhydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.The reaction is carried out in a solvent, such as ethanol, methanol,tetrahydrofuran, acetone, or butanone. The product may be isolated fromthe reaction zone by evaporation and extraction and may be purified bymethods well known in the art, such as chromatography andrecrystallization.

In Scheme E, step c, a N-ω-aminoalkyl-N-acetyl-4-aminobenzophenone ofstructure 19 is olefinated using an appropriate α-chloro or α-bromophosphorous reagent to give a N-(ω-aminoalkyl)acetamido-triaryl-ethyleneof structure 17.

An appropriate α-chloro or α-bromo phosphorous reagent is one which R₆is as defined in Scheme C, step a, X is chloro or bromo, M is lithium,sodium, or potassium, and G is P(Ph)₃, P(O)(OPh)₂, P(O)(OCH₂ CH₃)₂,P(O)(OCH₃)₂, or P(O)(OCH(CH₃)₂)₂. The preparation and use of appropriateα-chloro or α-bromo phosphorous reagents well known and appreciated inthe art, such as described in K. Lee et al., Syn. Comm. 22 649-655(1992); J. Petrova et al., Synthesis 658-660 (1975); M. D. Crenshaw andH. Zimmer J. Org. Chem. 48 2782-2784 (1983); T. Gajda, Synthesis 717-718(1990); T. Gajda, Phosphorous and Sulfur 53 327-331 (1990); and S. K.Chakoborty and R. Engle, Syn. Comm. 21 1039-1046 (1991). An appropriateα-chloro or α-bromo phosphorous reagent can be prepared and isolated orisolated and purified before use or can be prepared and used withoutisolation.

For example, a N-ω-aminoalkyl-N-acetyl-4-aminobenzophenone of structure19 is contacted with a slight excess of lithium diethyl α-chlorobenzylphosphonate. The reaction is carried out in a suitable solvent,such as THF, benzene or toluene. The reaction is performed attemperatures from -78° C. to the refluxing temperature of the solvent.The product can be isolated as generally taught in Scheme D, step c.

Alternately, a N-ω-aminoalkyl-N-acetyl-4-aminobenzophenone of structure19 is contacted with a slight excess of an anion derived from a α-chlorobenzyltriphenylphosphonium salt. The reaction is carried out in asuitable solvent, such as THF, or toluene. The reaction is performed attemperatures from -78° C. to the refluxing temperature of the solvent.The product can be isolated as generally taught in Scheme D, step c.

As generally taught in Scheme D, step d, the acetyl group of aN-(ω-aminoalkyl)acetamido-triaryl-ethylene of structure 17 is hydrolyzedto give an ω-aminoalkylamino-triaryl-ethylene of structure 13.

As generally taught in Scheme C, optional step e, anω-aminoalkylamino-triaryl-ethylene of structure 13 can be deprotectedand further modified as required to give aω-aminoalkylamino-triaryl-ethylene of structure 14.

As generally taught in Scheme C, step f, the isomers of aω-aminoalkylamino-triaryl-ethylene of structure 13 or 14 are separatedto give a (E)-ω-aminoalkylamino-triaryl-ethylene and the(Z)-ω-aminoalkylamino-triaryl-ethylene.

EXAMPLE 59

N-Acetyl-4-aminobenzophenone

Combine 4-aminobenzophenone (10.0 g, 50.8 mmol), acetic anhydride (5.74mL, 60.9 mmol), and triethylamine (9.5 mL, 68.5 mmol) in toluene (30mL). Heat to reflux. After 2 hours, cool to ambient temperature and pourthe reaction mixture into water. Stir to give a solid. Collect the solidby filtration, rinse with water, and dry. Recrystallize fromacetonitrile to give the title compound. R_(f) =0.35 (silica gel, ethylacetate).

EXAMPLE 59.1

N-Acetyl-4-aminobenzophenone

Combine 4-aminobenzophenone (500 g, 2.54 mol) and triethylamine (307g,3.03 mol) in dichloromethane (2.54 L). Add acetic anhydride (313.9 g,3.07 mol). After 18 hours, add methanol (100 mL) and evaporate in vacuoto give a residue. Combine the residue and water (8 L) and stir to givea solid. Collect the solid by filtration, rinse repeatedly with water,and dry to give the title compound.

EXAMPLE 60

N-(2-Diethylaminoethyl)-N-acetyl-4-aminobenzophenone

Combine N-acetyl-4-aminobenzophenone (4.0 g, 16.7 mmol),2-diethylaminoethyl chloride hydrochloride (3.97 g, 23.1 mmol), andpowdered potassium hydroxide (2.81 g, 50.1 mmol) in acetone (30 mL).Heat to reflux. After 2 hours, cool and decant the solvent. Evaporatethe solvent in vacuo to give a residue. Partition the residue betweenwater and ethyl acetate. Separate the organic layer and extract withwater. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give the title compound: R_(f) =0.0-0.14 (streaks on silica gel,ethyl acetate).

EXAMPLE 60.1

N-(2-Diethylaminoethyl)-N-acetyl-4-aminobenzophenone

Combine N-acetyl-4-aminobenzophenone (250 g, 1.05 mol),2-diethylaminoethyl chloride hydrochloride (207.5 g, 1.20 mol), and 85%potassium hydroxide (140 g, 2.12 mol) in acetone (3 L). Heat to reflux.After 2 hours, cool and filter. Evaporate the filtrate in vacuo to givea residue. Combine the residue and t-butyl methyl ether (1 L) and water(2 L). Add aqueous 1M hydrochloric acid solution until the pH is about2.5. Separate the aqueous layer and extract several times with t-butylmethyl ether. Adjust the pH of the aqueous layer to 10 using aqueous 50%sodium hydroxide solution. Extract the aqueous layer twice withdichloromethane. Dry the combined dichlormethane layers over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting sequentially with ethyl acetate, 5/95methanol/ethyl acetate, 10/90 methanol/ethyl acetate to give the titlecompound: R_(f) =0.36 (silica gel, 2/8/0.1 methanol/ethylacetate/triethylamine).

EXAMPLE 61

(E and Z)-1-4-N-Acetyl-N-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine diethyl benzylphosphonate (1.23 mL, 5.91 mmol) and anhydroustetrahydrofuran (9.0 mL). Cool to -78° C. using a dry-ice-acetone bath.Add dropwise over 5 minutes a solution of n-butyllithium (4.73 mL, 2.5Min hexanes, 11.8 mmol). After 30 minutes, add benzenesulfonyl chloride(0.76 mL, 5.9 mmol). AddN-(2-diethylaminoethyl)-N-acetyl-4-aminobenzophenone (1.0 g, 2.96 mmol)in anhydrous tetrahydrofuran (6.0 mL). After 5 minutes at -78° C., warmto ambient temperature. After 30 minutes, add a saturated aqueoussolution of ammonium chloride (20 mL) and extract with ethyl acetate.Separate the organic layer and extract with a saturated aqueous solutionof sodium bicarbonate, dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 5/94.9/0.1 methanol/ethyl acetate/triethylamineto give the title compound (>2.5/1 E/Z): R_(f) =0.27 (silica gel,20/80/0.05 methanol/ethyl acetate/triethylamine).

EXAMPLE 61.1

(E and Z)-1-4-N-Acetyl-N-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine diethyl benzylphosphonate (42.9 g, 187 mmol) and anhydroustetrahydrofuran (350 mL). Cool to -60° C. Add dropwise a solution ofn-butyllithium (150 mL, 2.5M in hexanes, 375 mmol) while maintaining thetemperature at less than about -55° C. After 30 minutes, add a solutionof benzenesulfonyl chloride (32.8 g, 187 mmol) in tetrahydrofuran (90mL) while maintaining the temperature at less than about -55° C. After15 minutes, warm the reaction mixture to -30° C. After 15 minutes, coolto -55° C. Add by cannula to a cooled (-55° C.) solution ofN-(2-diethylaminoethyl)-N-acetyl-4-aminobenzophenone (55.0 g, 163 mmol)in anhydrous tetrahydrofuran (280 mL). The addition by cannula iscarried out while maintaining the temperature of the reaction mixture atless than about -45° C. After 10 minutes, warm slowly to ambienttemperature. After 30 minutes, add a saturated aqueous solution ofammonium chloride (500 mL) and extract with ethyl acetate (2.5 L).Separate the organic layer and extract with a saturated aqueous solutionof sodium bicarbonate, dry over MgSO₄, filter, and evaporate in vacuo togive a residue. Chromatograph the residue on silica gel elutingsequentially with 99.9/0.1 ethyl acetate/triethylamine and 5/94.9/0.1methanol/ethyl acetate/triethylamine to give the title compound.

EXAMPLE 62

(E and Z)-1-4-N-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene##STR46##

Combine (E and Z)-1-4-N-acetyl-N-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene(0.1 g, 0.22 mmol), potassium t-butoxide (0.16 g, 1.45 mmol), water (8.1μL, 0.45 mmol), and diethyl ether (1 mL). Heat to reflux. After 16hours, cool to ambient temperature, pour into ice-water and extract withethyl acetate. Separate the organic layer and extract with water andsaturated aqueous sodium chloride. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 5/94.9/0.1 methanol/ethylacetate/triethylamine to give the title compound (>2.5/1 E/Z): R_(f)=0.18 (silica gel, 20/80/0.05 methanol/ethyl acetate/triethylamine).

EXAMPLE 62.1

(E and Z)-1-4-N-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene

Combine (E and Z)-1-4-N-acetyl-N-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene(59.3 g, 133 mmol), potassium t-butoxide (95 g, 850 mmol), water (2.0mL), and tetrahydrofuran (1.0 L). Heat to reflux. After 1 hour, cool toambient temperature and partition between water and ethyl acetate.Separate the organic layer and extract with water and saturated aqueoussodium chloride. Dry the organic layer over MgSO₄, filter, and evaporatein vacuo to give the title compound.

EXAMPLE 63

(E)-1-4-N-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt ##STR47##

Combine (E and Z)-1-4-N-acetyl-N-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene(53.9 g, 133 mmol) and diethyl ether. Cool to about -5° C. Addhydrochloric acid (gas, 10.1 g, 280 mmol) over about 5 minutes whilemaintaining the temperature at about 5°-15° C. to give a solid. Collectthe solid by filtration, rinse with diethyl ether, and dry. Combine thesolid and acetone (375 mL). Heat to reflux. After 1.5 hours, cool toambient temperature and collect the solid by filtration, rinse withacetone. Combine the solid with tetrahydrofuran (450 mL) and heat toreflux. After 18 hours, cool to ambient temperature and collect thesolid by filtration, rinse with tetrahydrofuran. Again combine the solidwith tetrahydrofuran (400 mL) and heat at reflux. After 18 hours, coolto ambient temperature and collect the solid by filtration, rinse withtetrahydrofuran, and dry in vacuo to give the title compound (98.9%E-isomer).

EXAMPLE 64

(E)-1-4-N-(2-Diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylenecitric acid salt ##STR48##

Combine (E)-1-4-N-acetyl-N-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylenehydrochloride salt (27.6 g, 58 mmol) and ethyl acetate (350 mL).Carefully add with stirring a saturated aqueous solution of sodiumbicarbonate (200 mL). After 30 minutes, separate the organic layer andextract with a saturated aqueous solution of sodium chloride. Combinethe aqueous layers and extract with ethyl acetate. Dry the combinedorganic layers over MgSO₄, filter, and evaporate in vacuo to give aresidue. Combine the residue and acetone (300 mL), filter, and add asolution of citric acid (11.1 g, 57.8 mmol) in acetone (70 mL). Stir for5 hours to give a solid. Collect the solid by filtration, rinse withacetone, and dry in vacuo to give the title compound. Elemental Analysiscalculated for C₂₆ H₂₈ ClN₂.C₆ H₈ O₇ : C, 64.37; H, 6.25; N, 4.69.Found: C, 64.05; H, 6.19; N, 4.59.

EXAMPLE 65

Measurement of the Prevention of Bone Loss

Female, Sprague-Dawley rats weighing 200 to 225 grams each (70-75 daysof age) are obtained from Harlan Sprague Dawley, Inc. (Indianapolis,Ind.). For each compound, studies are carried out on four groups ofanimals as follows: Group 1 consists of 5 to 20 ovariectomized ratstreated with test compound at typical doses of 0.001 to 10 mg/kg/day;Group 2 consists of 5 to 20 ovariectomized rats treated with vehicle;Group 3 consists of 5 to 20 sham ovariectomized rats (incision made butovaries not removed) treated with test compound at typical doses of0.001 to 10 mg/kg/day; Group 4 consists of 5 to 20 sham ovariectomizedrats treated with vehicle. All rats are housed individually in suspendedwire cages and provided standard rodent laboratory pellets (Purina#5001) and deionized water adlibitum.

The test compound is homogenized in distilled water containing lecithin(10 mg/ml), sodium methylparaben (1.05 mg/ml) and sodium propylparaben(0.23 mg/ml). Compound and vehicle are administered daily for 40consecutive days by gavage in a volume of 5 ml/kg. Treatment isinitiated on the day following ovariectomy or sham ovariectomy.Twenty-four hours after the final administration of test compound (orvehicle) the rats are sacrificed, the hind limbs removed, dissected freeof the bulk of soft tissue and then placed in 10% buffered formalinuntil further processed. Complete ovariectomy is verified at the time ofsacrifice and rats with fragments of ovarian tissue are excluded.

After a minimum of one week in formalin, the femurs and tibias arecarefully dissected free of each other and remaining soft tissue. Thefemurs are then air dried for a minimum of 48 hours and radiographed ina Faxitron X-ray cabinet (Hewlett-Packard, McMinnville Oreg.) usingKodak XK-1 film exposed for 9 seconds at a tube voltage of 60 kV. Imagesof radiographs are captured using a CCD-72 solid-state video camera(Dage-MTI Inc., Michigan City, Ind.) equipped with a 50 mm (1:1.8) Nikonlens and a +1 or combined +4, +2, and +1 close-up lenses depending onthe desired magnification. The captured images are digitized with a CFGframegrabber (Imaging Technology Inc., Bedford Mass.) and analyzed usingOptimas image analysis software (Bioscan Inc., Edmonds Wash.).

Bone density (i.e., gray value of radiographic images) is measured atthe distal femur. Cancellous bone loss is measured at the proximaltibia. Decreased gray value variance reflects the loss of fine structureof bone present in radiographs.

Image analysis measurements are made as follows: For determination ofthe gray values of femurs, images are precisely orientated on themonitor using screen templates and analysis region (2.30 mm×3.34 mm;11250 pixels) is superimposed over the digitized images at the distalfemur at approximately 1.2 mm proximal to the border of the medial andlateral condyles. The gray value of each picture element within theanalysis region is then measured and the mean gray value calculated byOptimas image analysis software (BioScan Inc; Edmondes, Wash.). Tominimize the effect of random noise on gray value measurements, twoimages of the analysis region are captured and averaged. The averagedimage is then treated with a 3×3 smoothing filter to yield the finalimage for gray value measurements. In addition to mean gray value, grayvalue variance is also determined at the distal femur using the sameanalysis region used for determining mean gray value.

To control for variability in gray value measurements potentiallyarising from the radiographic and imaging procedures, gray values areconverted to Density Units using standard curves prepared from grayvalue measurements collected from a 10-step aluminum wedge radiographedalong with the specimens on each film.

After removal from the formalin, tibias are placed in labeled tissuecassettes, decalcified, imbedded in parraffin, cut in 5 micron sagittalsections which are stained with aniline blue (a differential stain forbone). Trabecular bone loss is measured directly from stained sectionsof the proximal tibia.

For measuring trabecular bone area, tibia section images are preciselyorientated on a moniter screen template and a analysis region (1.17mm×1.54 mm; 18240 pixels) centered over the image between thecortico-medullary margins and positioned 1.0 mm from the growth plate atthe closest point. Optimas then determines the area of both the analysisregion and the trabecular bone within the region (in mm²) and calculatedthe percent of the region occupied by trabecular bone.

Statistical comparisons are done using Data Desk Professional software(Odesta Corp., Northbrook Ill.). Comparisons between groups are madeusing the two-tailed t test for independent means with a pooled estimateof variance. Values for the right and left femurs are averaged for eachanimal and the combined values used to calculate descriptive statisticsand for t tests. Statistical significance is assigned at P≦0.05 andP≦0.01.

EXAMPLE 66

Measurement of Serum Osteocalcin

For each compound, studies are carried out on four groups a animals asdescribed in Example 65. Anesthetize each animal with CO₂, collect bloodby cardiocentesis into clot-activating serum separator tubes. Collectthe serum by centrifugation and stored at -20° C.

Serum osteocalcin levels are measured by radioimmunoassay using themethod recommended by Biomedical Technologies, Inc. from whom therequired reagents are purchased. Serum is diluted 1:20 and either 100 μlof diluted sample or 100 μl rat osteocalcin standard (BT-412) is addedto 100 μl of rat osteocalcin primary antibody (goat anti-ratosteocalcin, BT-413), 100 μl normal goat nonimmune serum (NIS) and RIAbuffer 122.5 mM NaCl, 25 mM Na₄ EDTA, 10 mM NaH₂ PO₄, pH 7.4, 0.1% Tween20 and 0.1% bovine serum albumin (RIA grade)! to give a total volume of500 μl. Incubate at 4° C. overnight on an orbital platform shaker (120rpm). The second day, ¹²⁵ I!-rat osteocalcin (BT-411R) is added in 100μl (approximately 20,000 cpm) to compete with bound osteocalcin. Tubesare vortexed, then incubate overnight at 4° C. on an orbital shaker. Onday three, 1 ml of precipitating second antibody 2% donkey anti-goat lgG(BT-414) in 0.1M sodium phosphate buffer, pH 7.4, containing 2.5%polyethylene glycol and 0.05% NaN₃ ! is then added. The samples aremixed and incubated for 2 h at 4° C. on an orbital shaker, followed bysedimentation by centrifugation at 1500×g for 15 min at 4° C. Thesupernatant is carefully discarded and the pellets washed twice bycentrifugation with 500 μl distilled water. Supernatant is discarded andthe radioactivity associated with the pellet quantitated (2 min) usingan LKB gamma counter. Osteocalcin standards run in parallel are used fordetermination of standard osteocalcin values. Statistical analysis forosteocalcin measurements is carried out using Instat software to do atwo-sided T-test.

An embodiment of the present invention provides a method for thetreatment of a patient afflicted with bone tissue loss or osteoporosiscomprising the administration thereto of a effective antiosteoporosisamount of a compound of Formula I, II, III, or IV.

The terms "bone tissue loss" as used herein refers to a disease orcondition in which bone mass or density is decreased by the loss of bothmineral and protein matrix components resulting in bone fragility.

The term "osteoporosis" as used herein refers to a disease or conditionin which bone tissue loss is responsible for bone fragility resulting inone or more bone fractures.

As used herein, "an effective antiosteoporosis amount" of a compound ofFormula I, II, III, or IV refers to an amount which is effective, uponsingle or multiple dose administration to the patient, in preventing ordecreasing the rate of bone tissue loss in the patient beyond thatexpected in the absence of such treatment.

Identification of patients in need of treatment for bone tissue loss orosteoporosis is well within the ability and knowledge of one skilled inthe art. The methods for identification of patients which are at risk ofdeveloping bone tissue loss or osteoporosis are known and appreciated inthe medical arts, such as family history of the development of bonetissue loss or osteoporosis and the presence of risk factors associatedwith the development of bone tissue loss or osteoporosis. A clinicianskilled in the art can readily identify, by the use of clinical tests,physical examination and medical/family history, those patients who areat risk of developing bone tissue loss or osteoporosis and thus readilydetermine if an individual is a patient in need of prophylactictreatment for bone tissue loss or osteoporosis.

An effective antiosteoporosis amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use of knowntechniques and by observing results obtained under analogouscircumstances. In determining the effective antiosteoporosis amount ordose a number of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the degree of or involvement or the severity of thedisease; the response of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances.

An effective antiosteoporosis amount of a compound of Formula I, II,III, or IV is expected to vary from about 0.001 milligram per kilogramof body weight per day (mg/kg/day) to about 100 mg/kg/day.

In a further embodiment, the present invention provides for a method ofincreasing bone mass and preventing bone tissue loss or osteoporosis ina patient, comprising administering an effective antiosteoporosis amountof a compound of the Formula I, II, III, or IV.

As used herein, the term "patient" refers to a warm-blooded animal, suchas a mouse, a rat, a hamster, a rabbit, or a human, which is afflictedwith bone tissue loss or osteoporosis or is at risk of developing bonetissue loss or osteoporosis or who is in need of treatment for bonetissue loss or osteoporosis.

In effecting treatment of a patient afflicted with the disease statesdescribed above or in effecting prophylactic treatment of a patient whomay be afflicted with the disease states as described above, a compoundof Formula I, II, III, or IV can be administered in any form or modewhich makes the compound bioavailable in effective amounts, includingoral and parenteral routes. For example, compounds of Formula I, II,III, or IV can be administered orally, subcutaneously, intramuscularly,intravenously, transdermally, intranasally, rectally, and the like. Oraladministration is generally preferred. One skilled in the art ofpreparing formulations can readily select the proper form and mode ofadministration depending upon the particular characteristics of thecompound selected the disease state to be treated, the stage of thedisease, and other relevant circumstances.

The compounds of Formula I, II, III, or IV can be administered alone orin the form of a pharmaceutical composition in combination withpharmaceutically acceptable carriers or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the invention, whileeffective themselves, may be formulated and administered in the form oftheir pharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

In another embodiment, the present invention provides compositionscomprising a compound of Formula I, II, III, or IV in admixture orotherwise in association with one or more inert carriers. Thesecompositions are useful, for example, as assay standards, as convenientmeans of making bulk shipments, or as pharmaceutical compositions. Anassayable amount of a compound of Formula I, II, III, or IV is an amountwhich is readily measurable by standard assay procedures and techniquesas are well known and appreciated by those skilled in the art. Assayableamounts of a compound of Formula I, II, III, or IV will generally varyfrom about 0.001% to about 75% of the composition by weight. Inertcarriers can be any material which does not degrade or otherwisecovalently react with a compound of Formula I, II, III, or IV. Examplesof suitable inert carriers are water; aqueous buffers, such as thosewhich are generally useful in High Performance Liquid Chromatography(HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate,hexane and the like; and pharmaceutically acceptable carriers orexcipients.

More particularly, the present invention provides pharmaceuticalcompositions comprising an effective antiosteoporosis amount of acompound of Formula I, II, III, or IV in admixture or otherwise inassociation with one or more pharmaceutically acceptable carriers orexcipients.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted for oralor parenteral use and may be administered to the patient in the form oftablets, capsules, suppositories, solution, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the compound of theinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the compound present in compositionsis such that a suitable dosage will be obtained. Preferred compositionsand preparations according to the present invention are prepared so thatan oral dosage unit form contains between 5.0-300 milligrams of acompound of the invention.

The tablets, pills, capsules, troches and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the inventive compound presentin such compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.1 to 100 milligrams of the compound of the invention.

The solutions or suspensions may also include the one or more of thefollowing adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

As with any group of structurally related compounds which possesses aparticular generic utility, certain groups and configurations arepreferred for compounds of Formulas I and II in their end-useapplication.

With respect to the substituent X, compounds of Formula I, II, III, andIV wherein X is chloro are generally preferred.

With respect to the substituent A, compounds of Formula I, II, III, andIV wherein A is diethylamino are generally preferred.

What is claimed is:
 1. A method of treating bone tissue loss orosteoporosis in a patient, comprising administering an effectiveantiosteoporosis amount of a compound of the formula ##STR49## wherein Ais a radical of the formula ##STR50## wherein R and R₁ are eachindependently hydrogen or C₁ -C₄ alkyl; andG is HN, H₃ CN, CH₂, or O; wis an integer from 2 to 3; R₂ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,halogen, or hydroxy; R₃ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,halogen, hydroxy, or --Y(CH₂)_(z) A₁ in which A₁ is a radical of theformula ##STR51## wherein Y is --HN--;R₄ and R₅ are each independentlyhydrogen or C₁ -C₄ alkyl; G₁ is HN, H₃ CN, CH₂, or O; and z is aninteger from 2 to 3; X is chloro or bromo;or a pharmaceuticallyacceptable salt thereof.
 2. A method according to claim 1 wherein w is2.
 3. A method according to claim 1 wherein A is the radical ##STR52##wherein R and R₁ are each independently hydrogen or C₁ -C₄ alkyl.
 4. Amethod according to claim 3 wherein R and R₁ are each independently C₁-C₄ alkyl.
 5. A method according to claim 4 wherein R and R₁ are eachethyl.
 6. A method according to claim 1 wherein R₃ is hydrogen.
 7. Amethod according to claim 1 wherein X is chloro.
 8. A method accordingto claim 1 wherein the compound is (E)-1-4-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene.
 9. Amethod of treating bone tissue loss or osteoporosis in a patient,comprising administering an effective antiosteoporosis amount of acompound of the formula ##STR53## wherein A is a radical of the formula##STR54## wherein R and R₁ are each independently hydrogen or C₁ -C₄alkyl; andG is HN, H₃ CN, CH₂, or O; w is an integer from 2 to 3; R₂ ishydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, or hydroxy; R₃ ishydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, hydroxy, or --Y(CH₂)_(z)A₁ in which A₁ is a radical of the formula ##STR55## wherein Y is--HN--;R₄ and R₅ are each independently hydrogen or C₁ -C₄ alkyl; G₁ isHN, H₃ CN, CH₂, or O; and z is an integer from 2 to 3; X is chloro orbromo;or a pharmaceutically acceptable salt thereof.
 10. A methodaccording to claim 9 wherein w is
 2. 11. A method according to claim 9wherein A is the radical ##STR56## wherein R and R₁ are eachindependently hydrogen or C₁ -C₄ alkyl.
 12. A method according to claim11 wherein R and R₁ are each independently C₁ -C₄ alkyl.
 13. A methodaccording to claim 12 wherein R and R₁ are each ethyl.
 14. A methodaccording to claim 9 wherein R₃ is hydrogen.
 15. A method according toclaim 9 wherein X is chloro.
 16. A method according to claim 9 whereinthe compound is (Z)-1-4-(2-diethylaminoethylamino)phenyl!-1,2-diphenyl-2-chloro-ethylene.